Anticholinergics, processes for preparing them, and pharmaceutical compositions containing them

ABSTRACT

A compound of formula 1  
                 
 
     wherein:  
     A is a group selected from  
                 
 
     X −  is an anion with a single negative charge;  
     R 1  and R 2  are each independently a C 1 -C 4 -alkyl optionally substituted with hydroxy or halogen; and  
     R 3 , R 4 , R 5 , R 6 , R 7 , and R 8  are each independently hydrogen, C 1 -C 4 -alkyl, C 1 -C 4 -alkyloxy, hydroxy, CF 3 , CN, NO 2 , or halogen,  
     with the proviso that at least one of the groups R 3 , R 4 , R 5 , R 6 , R 7 , and R 8  is not hydrogen, processes for preparing these compounds, pharmaceutical compositions containing these compounds, and their use as pharmaceutical compositions.

RELATED APPLICATIONS

[0001] Benefit under 35 U.S.C. § 119(e) of prior U.S. provisionalapplication Serial No. 60/249,350, filed Nov. 16, 2000, is herebyclaimed.

BACKGROUND OF THE INVENTION

[0002] The present invention relates to new anticholinergics of generalformula 1

[0003] wherein A, X⁻, and the groups R¹, R², R³, R⁴, R⁵, R⁶, R⁷, and R⁸have the meanings given herein, processes for preparing them, and theiruse as pharmaceutical compositions.

[0004] Anticholinergics may be used therapeutically in a variety ofcomplaints. Particular mention should be made here, for example, of thetreatment of asthma or chronic obstructive pulmonary disease (COPD). Fortreating these diseases WO 92/16528 proposes anticholinergics which havea scopine, tropenol, or tropine basic structure. The objective on whichWO 92/16528 is based is to prepare compounds with an anticholinergicactivity which are characterized by a long-lasting activity. To solvethis problem, WO 92/16528 discloses, inter alia, benzilic acid esters ofscopine, tropenol, or tropine.

[0005] For treating chronic diseases it is often desirable to preparepharmaceutical compositions having a fairly long duration of activity.As a rule, this ensures that the concentration of the active substanceneeded in the body to achieve the therapeutic effect is provided over afairly long period of time without having to administer the drug toofrequently. Moreover, administering an active substance at fairly longtime intervals makes a major contribution to the patient's well being.It is particularly desirable to provide a drug which can be used in atherapeutically beneficial manner by a single application per day(single dose). The use of a drug once a day has the advantage that thepatient can become accustomed relatively quickly to regularly taking thedrug at certain times of the day.

[0006] In order to be used as a medicament for use once a day, theactive substance to be given must meet particular requirements. First ofall, the onset of the desired activity should take place relativelyquickly after administration of the drug and ideally should have asconstant an effect as possible over a subsequent fairly long period oftime. On the other hand, the duration of activity of the drug should notsubstantially exceed a period of about one day. Ideally, an activesubstance has an activity profile such that the preparation of a drugfor administration once a day, which contains the active substance intherapeutically beneficial doses, can be deliberately controlled.

[0007] It has been found that the benzilic acid esters of scopine,tropenol, and tropine disclosed in WO 92/16528 do not meet thesestringent requirements. Because of their extremely long period ofactivity, which significantly exceeds the above-mentioned period ofabout one day, they cannot be used therapeutically for administration ina single dose per day.

[0008] The aim of the present invention is therefore to provide newanticholinergics which, by virtue of their activity profile, make itpossible to prepare a drug for administration once a day. A furtherobjective of the invention is to prepare compounds characterized by arelative rapid onset of activity. The invention further sets out toprovide compounds which, after a rapid onset of activity, have asconstant an activity as possible over a subsequent lengthy period oftime. A further aim of the invention is to provide compounds whoseduration of activity does not substantially exceed a period of about oneday in therapeutically beneficial doses. Finally, the invention sets outto provide compounds which have an activity profile which ensures goodcontrol of the therapeutic effect (i.e., total therapeutic effectwithout side effects caused by a build-up of the substance in the body).

DETAILED DESCRIPTION OF THE INVENTION

[0009] Surprisingly, it has been found that the above objectives areachieved by means of compounds of general formula 1 wherein at least oneof the groups R³, R⁴, R⁵, R⁶, R⁷, and R⁸ does not represent hydrogen.

[0010] Accordingly, the present invention relates to compounds ofgeneral formula 1

[0011] wherein:

[0012] A denotes a double-bonded group selected from among

[0013] X⁻ denotes an anion with a single negative charge;

[0014] R¹ and R² denote C₁-C₄-alkyl which is optionally substituted byhydroxy or halogen; and

[0015] R³, R⁴, R⁵, R⁶, R⁷, and R⁸, which may be identical or different,denote hydrogen, C₁-C₄-alkyl, C₁-C₄-alkyloxy, hydroxy, CF₃, CN, NO₂, orhalogen, with the proviso that at least one of the groups R³, R⁴, R⁵,R⁶, R⁷, and R⁸ is not hydrogen.

[0016] Preferred compounds of general formula 1 are those wherein Adenotes a double bonded group selected from among

[0017] X⁻ denotes an anion with a single negative charge selected fromamong chloride, bromide, methylsulfate, 4-toluenesulfonate, andmethanesulfonate, preferably bromide;

[0018] R¹ and R², which may be identical or different, denote a groupselected from among methyl, ethyl, n-propyl, and isopropyl, which isoptionally substituted by hydroxy or fluorine, preferably unsubstitutedmethyl; and

[0019] R³, R⁴, R⁵, R⁶, R⁷, and R⁸, which may be identical or different,denote hydrogen, methyl, ethyl, methyloxy, ethyloxy, hydroxy, fluorine,chlorine, bromine, CN, CF₃, or NO₂, with the proviso that at least oneof the groups R³, R⁴, R⁵, R⁶, R⁷, and R⁸ is not hydrogen.

[0020] Particularly preferred are compounds of general formula 1,wherein A denotes a double-bonded group selected from among

[0021] X⁻ denotes bromide;

[0022] R¹ and R², which may be identical or different, denote methyl orethyl, preferably methyl; and

[0023] R³, R⁴, R⁵, R⁶, R⁷, and R⁸, which may be identical or different,denote hydrogen, methyl, methyloxy, fluorine, chlorine, or bromine, withthe proviso that at least one of the groups R³, R⁴, R⁵, R⁶, R⁷, and R⁸is not hydrogen.

[0024] Of particular importance according to the invention are compoundsof general formula 1, wherein A denotes a double-bonded group selectedfrom among

[0025] X⁻ denotes bromide;

[0026] R¹ and R², which may be identical or different, denote methyl orethyl, preferably methyl; and

[0027] R³, R⁴, R⁵, R⁶, R⁷, and R⁸, which may be identical or different,denote hydrogen, fluorine, chlorine, or bromine, with the proviso thatat least one of the groups R³, R⁴, R⁵, R⁶, R⁷, and R⁸ is not hydrogen.

[0028] Also of particular importance according to the invention arecompounds of general formula 1, wherein A denotes a double-bonded groupselected from among

[0029] X⁻ denotes bromide;

[0030] R¹ and R² which may be identical or different denote methyl orethyl, preferably methyl; and

[0031] R³, R⁴, R⁵, R⁶, R⁷, and R⁸, which may be identical or different,denote hydrogen, fluorine, chlorine, or bromine, with the proviso thatat least one of the groups R³, R⁴, R⁵, R⁶, R⁷, and R⁸ is not hydrogen.

[0032] Of outstanding importance according to the invention are thecompounds of general formula 1, wherein A denotes a double-bonded groupselected from among

[0033] X⁻ denotes bromide; R¹ and R² denote methyl; and R³, R⁴, R⁵, R⁶,R⁷, and R⁸, which may be identical or different, denote hydrogen orfluorine, with the proviso that at least one of the groups R³, R⁴, R⁵,R⁶, R⁷, and R⁸ is not hydrogen.

[0034] The invention relates to the compounds of formula 1, optionallyin the form of the individual optical isomers, mixtures of theindividual enantiomers, or racemates thereof.

[0035] In the compounds of general formula 1 the group R³, R⁴, R⁵, R⁶,R⁷, and R⁸, provided that they do not denote hydrogen, may each be inthe ortho-, meta-, orpara-position relative to the bond to the“—C—OH”—group. Provided that none of the groups R³, R⁴, R⁵, R⁶, R⁷, andR⁸ denotes hydrogen, R³ and R⁵ are preferably linked in thepara-position and R⁴, R⁶, R⁷, and R⁸ are preferably linked in the ortho-or meta-position, most preferably in the meta-position. Particularlypreferred are compounds of formula 1 wherein the groups R⁷ and R⁸ denotehydrogen. If in this case one of the groups R³ and R⁴ and one of thegroups R⁵ and R⁶ denotes hydrogen, the other group in each case ispreferably linked in the meta- or para-position, most preferably in thepara-position. If none of the groups R³, R⁴, R⁵, R⁶, R⁷, and R⁸ denoteshydrogen, according to the invention the compounds of general formula 1wherein the groups R³, R⁴, R⁵, R⁶, R⁷, and R⁸ have the same meaning areparticularly preferred.

[0036] Of particular importance according to the invention are thecompounds of general formula 1 wherein the ester-substituent on thenitrogen-bicyclic group is in the α-configuration. These compoundscorrespond to general formula 1-α

[0037] The following compounds are of particular significance accordingto the invention:

[0038] (a) tropenol 3,3′,4,4′-tetrafluorobenzilate methobromide;

[0039] (b) scopine 3,3′,4,4′-tetrafluorobenzilate methobromide;

[0040] (c) scopine 4,4′-dichlorobenzilate methobromide;

[0041] (d) scopine 4,4′-difluorobenzilate methobromide;

[0042] (e) tropenol 3,3′-difluorobenzilate methobromide;

[0043] (f) scopine 3,3′-difluorobenzilate methobromide; and

[0044] (g) tropenol 4,4′-difluorobenzilate ethyl bromide.

[0045] Unless otherwise stated, the alkyl groups are straight-chained orbranched alkyl groups having 1 to 4 carbon atoms. The following arementioned by way of example: methyl, ethyl, propyl, or butyl. In somecases the abbreviations Me, Et, Prop, or Bu are used to denote thegroups methyl, ethyl, propyl, or butyl. Unless otherwise stated, thedefinitions propyl and butyl include all the possible isomeric forms ofthe groups in question. Thus, for example, propyl includes n-propyl andisopropyl, butyl includes isobutyl, sec-butyl, and tert-butyl, etc.

[0046] Unless otherwise stated, the term alkyloxy groups denotesbranched and unbranched alkyl groups having 1 to 4 carbon atoms whichare linked via an oxygen atom. Examples of these include: methyloxy,ethyloxy, propyloxy, or butyloxy. The abbreviations MeO—, EtO—, PropO—,or BuO— are used in some cases to denote the groups methyloxy, ethyloxy,propyloxy, or butyloxy. Unless otherwise stated, the definitionspropyloxy and butyloxy include all possible isomeric forms of the groupsin question. Thus, for example, propyloxy includes n-propyloxy andisopropyloxy, butyloxy includes isobutyloxy, sec-butyloxy, andtert-butyloxy, etc. In some cases, within the scope of the presentinvention, the term alkoxy is used instead of the term alkyloxy.Accordingly, the terms methoxy, ethoxy, propoxy, or butoxy may also beused to denote the groups methyloxy, ethyloxy, propyloxy, or butyloxy.

[0047] Halogen within the scope of the present invention denotesfluorine, chlorine, bromine, or iodine. Unless stated otherwise, bromineis the preferred halogen.

[0048] The compounds according to the invention may partly be prepared,as illustrated below, analogously to procedures which are already knownfrom the prior art (Diagram 1).

[0049] Diagram 1

[0050] Starting from the compounds of formula 2, the esters of generalformula 4 may be obtained by reacting with the benzilic acid esters offormula 3, wherein R denotes a C₁-C₄-alkyl group, for example. Thisreaction may be carried out, for example, in a sodium melt at elevatedtemperature, preferably at about 50° C.-150° C., particularly preferablyat about 90° C.-100° C. at low pressure, preferably below 500 mbar, mostpreferably below 75 mbar. Alternatively, instead of the benzilic acidesters 3, the corresponding α-chlorine compounds may be used (Cl insteadof OH). In this case the reaction may be carried out analogously to theexamples of synthesis disclosed in WO 92/16528, to which reference ishereby made in its entirety. The compounds of formula 4 thus obtainedcan be converted into the target compounds of formula 1 by reacting withthe compounds R²-X wherein R² and X may be as hereinbefore defined. Thissynthesis step may also be carried out analogously to the examples ofsynthesis disclosed in WO 92/16528.

[0051] Alternatively to the method of synthesizing the compounds offormula 4 illustrated in Diagram 1, the derivatives 4 wherein thenitrogen bicyclic group denotes a scopine-derivative may be obtained byoxidizing compounds of formula 4 wherein the bicyclic nitrogen group isa tropenyl group. This may be done as follows, according to theinvention.

[0052] The compound 4 wherein A denotes —CH═CH—, is suspended in a polarorganic solvent, preferably in a solvent selected from amongN-methyl-2-pyrrolidone (NMP), dimethylacetamide, and dimethylformamide,preferably dimethylformamide, and then heated to a temperature of about30° C.-90° C., preferably 40° C.-70° C. Then a suitable oxidizing agentis added and the mixture is stirred at constant temperature for 2 to 8hours, preferably 3 to 6 hours. The preferred oxidizing agent isvanadium pentoxide mixed with H₂O₂, most preferably H₂O₂-urea complexcombined with vanadium pentoxide. The mixture is worked up in the usualway. The products may be purified by crystallization or chromatography,depending on their crystallization tendencies.

[0053] As shown in Diagram 1, the intermediate products of generalformula 4 are of crucial importance. Accordingly, in another aspect, thepresent invention relates to the intermediates of formula 4

[0054] wherein:

[0055] A denotes a double-bonded group selected from among

[0056] R¹ denotes C₁-C₄-alkyl which is optionally substituted by hydroxyor halogen; and

[0057] R³, R⁴, R⁵, R⁶, R⁷, and R⁸, which may be identical or different,denote hydrogen, C₁-C₄-alkyl, C₁-C₄-alkyloxy, hydroxy, CF₃, CN, NO₂, orhalogen, with the proviso that at least one of the groups R³, R⁴, R⁵,R⁶, R⁷, and R⁸ is not hydrogen.

[0058] The intermediates of general formula 4 are preferred wherein Adenotes a double-bonded group selected from among

[0059] R¹ methyl, ethyl, n-propyl, and isopropyl, which is optionallysubstituted by hydroxy or fluorine, preferably unsubstituted methyl; and

[0060] R³, R⁴, R⁵, R⁶, R⁷, and R⁸, which may be identical or different,denote hydrogen, methyl, ethyl, methyloxy, ethyloxy, hydroxy, fluorine,chlorine, bromine, CN, CF₃, or NO₂, with the proviso that at least oneof the groups R³, R⁴, R⁵, R⁶, R⁷, and R⁸ is not hydrogen.

[0061] Particularly preferred are the intermediates of general formula4, wherein A denotes a double-bonded group selected from among

[0062] R¹ denotes methyl or ethyl, preferably methyl; and

[0063] R³, R⁴, R⁵, R⁶, R⁷, and R⁸, which may be identical or different,denote hydrogen, methyl, methyloxy, fluorine, chlorine, or bromine, withthe proviso that at least one of the groups R³, R⁴, R⁵, R⁶, R⁷, and R⁸is not hydrogen.

[0064] Of particular importance according to the invention are theintermediates of general formula 4, wherein A denotes a double-bondedgroup selected from among

[0065] R¹ denotes methyl or ethyl, preferably methyl; and

[0066] R³, R⁴, R⁵, R⁶, R⁷, and R⁸, which may be identical or different,denote hydrogen, fluorine, chlorine, or bromine, with the proviso thatat least one of the groups R³, R⁴, R⁵, R⁶, R⁷, and R⁸ is not hydrogen.

[0067] Also of particular importance according to the invention are theintermediates of formula 4, wherein A denotes a double-bonded groupselected from among

[0068] R¹ denotes methyl or ethyl, preferably methyl; and

[0069] R³, R⁴, R⁵, R⁶, R⁷, and R⁸, which may be identical or different,denote hydrogen, fluorine, chlorine, or bromine, with the proviso thatat least one of the groups R³, R⁴, R⁵, R⁶, R⁷, and R⁸ is not hydrogen.

[0070] Of exceptional importance according to the invention are theintermediates of general formula 4 wherein A denotes a double-bondedgroup selected from among

[0071] R¹ denotes methyl; and

[0072] R³, R⁴, R⁵, R⁶, R⁷, and R⁸, which may be identical or different,denote hydrogen or fluorine, with the proviso that at least one of thegroups R³, R⁴, R⁵, R⁶, R⁷, and R⁸ is not hydrogen.

[0073] As in the compounds of general formula 1, in the intermediates offormula 4 the groups R³, R⁴, R⁵, R⁶, R⁷, and R⁸, if they do notrepresent hydrogen, may be in the ortho-, meta-, or para-positionrelative to the bond to the “—C—OH” group. If none of the groups R³, R⁴,R⁵, R⁶, R⁷, and R⁸ denotes hydrogen, R³ and R⁵ are preferably linked inthe para-position and R⁴, R⁶, R⁷, and R⁸ are preferably linked in theortho- or meta-position, most preferably in the meta-position.Particularly preferred are intermediates of formula 4 wherein R⁷ and R⁸denote hydrogen. If in this case one of the groups R³ and R⁴ and one ofthe groups R⁵ and R⁶ denote hydrogen, the other group in each case ispreferably linked in the meta- orpara-position, most preferably in thepara-position. If none of the groups R³, R⁴, R⁵, R⁶, R⁷, and R⁸ denoteshydrogen, according to the invention the intermediates of generalformula 4 wherein the groups R³, R⁴, R⁵, R⁶, R⁷, and R⁸ have the samemeaning are particularly preferred.

[0074] In order to prepare the intermediate products of general formula4, correspondingly substituted benzilic acid derivatives of generalformula 3 are used. These are obtained, analogously to methods known inthe art, by reacting Grignard reagents generated in situ from thebromides 5 with the aromatic α-carbonyl-carboxylic acid esters 6.

[0075] Diagram 2

[0076] The reaction is carried out in anhydrous organic solvents,preferably in ethereal solvents, most preferably in a solvent selectedfrom among diethylether, dioxane, and tetrahydrofuran (THF), the latterbeing particularly significant. The Grignard reagent is generated fromthe bromides 5 by reacting with Mg chips. In some cases it may benecessary to add a reaction starter such as iodine or dibromoethane. Inorder to complete the formation of Grignard-reagent it may be necessaryto heat the reaction mixture over a period of 0.5 to 2 hours, preferablyto above 30° C., most preferably to above 50° C. The upper limit of thetemperature range which may be used will naturally be determined fromthe boiling temperature of the solvent used. The Grignard-reagent thusobtained is then slowly added dropwise to a solution of 6 in one of theabove-mentioned solvents. The work may be done at ambient temperature,but is preferably done at a temperature in the range from 0° C.-15° C.The reaction is generally complete after 1 to 4 hours. The mixture isworked up by conventional methods. The products are purified bycrystallization or column chromatography, depending on thecrystallization tendencies of the compounds 3.

[0077] Alternatively, the compounds of formula 3 may also be obtainedanalogously to other methods of synthesis known from the prior art.Where, for example, suitably substituted benzilic acids are alreadyknown in the art and are commercially available, the compounds offormula 3 may also be obtained directly from them by acid- orbase-catalyzed esterification with the corresponding alcohols R—OH.Where suitably substituted benzils are already known from the art andare commercially available, the compounds of formula 3 may also beobtained directly from them by benzilic acid rearrangement andsubsequent acid- or base-catalyzed esterification with the correspondingalcohols R—OH.

[0078] As can be seen from Diagram 1, the benzilic acid derivatives ofgeneral formula 3 have a central importance in preparing the compoundsof general formula 4 and thus those of formula 1 as well.

[0079] Accordingly, in another aspect, the present invention relates tobenzilic acid derivatives of general formula 3

[0080] wherein:

[0081] R denotes C₁-C₄-alkyl, preferably methyl or ethyl; and

[0082] R³, R⁴, R⁵, R⁶, R⁷, and R⁸, which may be identical or different,denote hydrogen, C₁-C₄-alkyl, C₁-C₄-alkyloxy, hydroxy, CN, CF₃, NO₂, orhalogen, with the proviso that at least one of the groups R³, R⁴, R⁵,R⁶, R⁷, and R⁸ is not hydrogen.

[0083] Preferred are benzilic acid derivatives of general formula 3,wherein R denotes methyl or ethyl; and R³, R⁴, R⁵, R⁶, R⁷, and R⁸, whichmay be identical or different, denote hydrogen, methyl, ethyl,methyloxy, ethyloxy, hydroxy, fluorine, chlorine, bromine, CN, CF₃, orNO₂, with the proviso that at least one of the groups R³, R⁴, R⁵, R⁶,R⁷, and R⁸ is not hydrogen.

[0084] Particularly preferred are benzilic acid derivatives of generalformula 3, wherein R denotes methyl or ethyl; and R³, R⁴, R⁵, R⁶, R⁷,and R⁸, which may be identical or different, denote hydrogen, methyl,methyloxy, fluorine, chlorine, or bromine, with the proviso that atleast one of the groups R³, R⁴, R⁵, R⁶, R⁷, and R⁸ is not hydrogen.

[0085] Of particular importance according to the invention are benzilicacid derivatives of general formula 3, wherein R denotes methyl orethyl; and R³, R⁴, R⁵, R⁶, R⁷, and R⁸, which may be identical ordifferent, denote hydrogen, fluorine, chlorine, or bromine, with theproviso that at least one of the groups R³, R⁴, R⁵, R⁶, R⁷, and R⁸ isnot hydrogen.

[0086] Of exceptional importance according to the invention are theintermediates of general formula 3, wherein R denotes methyl or ethyl;and R³, R⁴, R⁵, R⁶, R⁷, and R⁸, which may be identical or different,denote hydrogen or fluorine, with the proviso that at least one of theR³, R⁴, R⁵, R⁶, R⁷, and R⁸ is not hydrogen.

[0087] As in the compounds of general formula 4 and 1, in the benzilicacid derivatives of formula 3 the groups R³, R⁴, R⁵, R⁶, R⁷, and R⁸,provided that they are not hydrogen, may each be in the ortho-, meta-,or para-position relative to the bond to the “—C—OH” group. If none ofthe groups R³, R⁴, R⁵, R⁶, R⁷, and R⁸ denotes hydrogen, R³ and R⁵ arepreferably linked in the para-position and R⁴, R⁶, R⁷, and R⁸ arepreferably linked in the ortho- or meta-position, most preferably in themeta-position. Particularly preferred are benzilic acids of formula 3wherein R⁷ and R⁸ denote hydrogen. If one of the groups R³ and R⁴ andone of the groups R⁵ and R⁶ denotes hydrogen, the other group in eachcase is preferably linked in the meta- or para-position, most preferablyin the para-position. If none of the groups R³, R⁴, R⁵, R⁶, R⁷, and R⁸denotes hydrogen, according to the invention the benzilic acidderivatives of general formula 3 wherein the groups R³, R⁴, R⁵, R⁶, R⁷,and R⁸ have the same meaning are particularly preferred.

[0088] The examples of synthesis described hereinafter serve toillustrate the present invention still further. However, they areintended only as examples of procedures as an illustration of theinvention without restricting the invention to the subject-matterdescribed by way of example.

[0089] I. Synthesis of the Benzilic Acid Derivatives of General Formula3

[0090] I.1: ethyl 3,3′,4,4′-tetrafluorobenzilate 3a

[0091] The Grignard reagent is prepared from 2.24 g (0.092 mol) ofmagnesium chips, a few granules of iodine, and 17.80 g (0.092 mol) of1-bromo-3,4-difluorobenzene in 100 ml of THF at 50° C. After the halidehas all been added, the mixture is stirred for another hour. TheGrignard reagent thus obtained is added dropwise to 18.81 g (0.088 mol)of ethyl 3,4-difluorophenylglyoxylate in 80 ml of THF at 10° C.-15° C.and the mixture obtained is stirred for 2 hours at 5° C. The whitesuspension is poured onto ice/sulfuric acid for working up, extractedwith ethyl acetate, the organic phase is washed with water, dried overMgSO₄ and evaporated to dryness. The crude product is purified by columnchromatography (eluant: toluene). Yield: 10.80 g (38% of theory).

[0092] I.2: methyl 2.2′-dichlorobenzilate 3b

[0093] A solution of 10.0 g (0.034 mol) of 2,2′-dichlorobenzilic acid in50 ml of ethanol was added dropwise to freshly prepared sodium ethoxidesolution of 0.78 g (0.034 mol) of sodium and 100 ml of ethanol at 20° C.and stirred overnight. The solution was evaporated to dryness, theresidue was dissolved in DMF and at 20° C. 9.57 g (0.0674 mol) of methyliodide were added dropwise and the mixture was stirred for a further 72hours. 300 ml of water were added dropwise to the resulting suspensionwhile cooling with ice, it was extracted with diethyl ether, the organicphase was washed with water, dried over Na₂SO₄, and evaporated todryness. Yield: 10.48 g (100% of theory).

[0094] I.3: methyl 4,4′-difluorobenzilate 3c

[0095] I.3.1: 4,4′-difluorobenzilic acid

[0096] At about 100° C., a solution of 24.62 g (0.1 mol) of4,4′-difluorobenzil in 250 ml of dioxane is added dropwise to a solutionof 49.99 g (1.25 mol) of NaOH flakes in 300 ml of water and stirred for2 hours. The dioxane is largely distilled off and the aqueous solutionremaining is extracted with dichloromethane. When the aqueous solutionis acidified with sulfuric acid, a precipitate is formed which issuction filtered, washed, and dried. The filtrate is extracted withdichloromethane, the organic phase is dried over Na₂SO₄ and evaporatedto dryness. Yield: 25.01 g (95% of theory); melting point: 133° C.-136°C.

[0097] I.3.2: methyl 4,4′-difluorobenzilate

[0098] 25.0 g (0.095 mol) of 4,4′-difluorobenzilic acid is added tofreshly prepared sodium ethoxide solution containing 2.17 g (0:095 mol)of sodium and 200 ml of ethanol at 20° C. and stirred for 3 hours. Thesolution is evaporated to dryness, the residue is dissolved in DMF,22.57 g (0.16 mol) of methyl iodide is added dropwise at 20° C., and themixture is stirred for 24 hours. It is worked up and purifiedanalogously to compound 3b. Yield: 21.06 g (80% of theory).

[0099] I.4: methyl 2,2′,4,4′-tetrafluorobenzilate 3d

[0100] I.4.1: methyl 2,4-difluorophenylglyoxylate

[0101] 50 g (0.44 mol) of 1,3-difluorobenzene is dissolved at 20° C. in135 ml of carbon disulfide with 73.5 g (0.55 mol) AlCl₃ and then 55.15 g(0.45 mol) of methyl oxalate chloride is added and the mixture isstirred for 2.5 hours at 20° C. Ice-cold 2 N aqueous hydrochloric acidis added dropwise while cooling, extracted with ethyl acetate; theorganic phase is washed with water and 10% aqueous Na₂CO₃ solution,dried over MgSO₄, and evaporated to dryness. Yield: 38.0 g (43% oftheory).

[0102] I4.2: methyl 2,2′,4,4′-tetrafluorobenzilate

[0103] Starting from the methyl 2,4-difluorophenylglyoxylate obtainedaccording to the above procedure, the title compound is preparedanalogously to 3a. Yield: 7.55 g (13% of theory).

[0104] I.5: methyl 4,4′-dimethylbenzilate 3e

[0105] At 20° C., 12.43 g (0.048 mol) of 4,4′-dimethylbenzilic acid in50 ml ethanol is added dropwise to freshly prepared sodium ethoxidesolution containing 1.1 g (0.045 mol) of sodium and 100 ml of ethanoland the mixture is stirred for 30 minutes. The solution is evaporated todryness, the residue dissolved in 50 ml of DMF, 9.08 g (0.064 mol) ofmethyl iodide is added dropwise at 20° C., and stirring is continued fora further 24 hours. 300 ml of water are added dropwise to the resultingsuspension while cooling with ice, the mixture is extracted withdiethylether; the organic phase is washed with water, dried over Na₂SO₄,and evaporated to dryness. Yield: 8.6 g (99% of theory); melting point:83° C.-84° C.

[0106] I.6: methyl 3,3′,4,4′-tetramethoxybenzilate 3f

[0107] I.6.1: methyl 3,4-dimethoxyglyoxylate:

[0108] 14.00 g (0.11 mol) of AlCl₃ are placed in 100 ml ofdichloromethane and at 5° C. combined with 12.86 g (0.11 mol) ofmonomethyl oxalate chloride. 1,2-dimethoxybenzene is added dropwise tothe organic solution at 0° C., the mixture is stirred for 1 hours at 0°C., then for 24 hours at 20° C., poured onto ice/hydrochloric acid, andextracted; the organic phase is washed with water and NaHCO₃ solution,dried over MgSO₄, and evaporated to dryness. The residue is crystallizedfrom diethylether/petroleum ether. Yield: 13.55 g (60% of theory);melting point: 65° C.-66° C.

[0109] I.6.2: methyl 3,3′,4,4′-tetramethoxybenzilate:

[0110] The Grignard reagent is prepared from 1.58 g (0.065 mol) ofmagnesium chips, some iodine, and 14.10 g (0.065 mol) of bromoveratrolein 50 ml of THF at 50° C. Stirring is continued for 1 hour. 11.28 g(0.05 mol) of methyl 3,4-dimethoxyglyoxylate are placed in 80 ml of THFand the Grignard reagent is added dropwise at 10° C.-15° C., the mixtureis stirred for 2 hours at 20° C., poured onto ice/sulfuric acid, andextracted with ethyl acetate. Then the organic phase is washed withwater, dried over MgSO₄, and evaporated to dryness. The product ispurified by crystallization from acetone/diethylether. Yield: 7.62 g(42% of theory); melting point:129° C.-130° C.

[0111] I.7: methyl 4,4′-dimethoxybenzilate 3g

[0112] I.7.1: methyl 4-methoxyglyoxylate:

[0113] The compound is prepared analogously to step I.6.1 starting from21.65 g (0.20 mol) of anisole; Yield: 16.45 g (60% of theory); meltingpoint: 52° C.

[0114] I.7.2: methyl 3,4-dimethoxybenzilate:

[0115] The compound is prepared analogously to step I.6.2, starting from16.45 g (0.085 mol) of methyl 4-methoxyglyoxylate; the product ispurified by crystallization from isopropanol; Yield: 12.28 g (48% oftheory); melting point: 111° C.

[0116] I.8: methyl 3,3′-dimethyl-4,4′-dimethoxybenzilate 3h

[0117] I.8.1: methyl 3-methyl-4-methoxyglyoxylate:

[0118] The compound is prepared analogously to step I.6.1 starting from26.88 g (0.22 mol) of 2-methylanisol. Yield: 21.0 g (46% of theory);melting point: 49° C.

[0119] I.8.2: methyl 3,4-dimethoxybenzilate:

[0120] The compound is prepared analogously to step I.6.2, starting from21.0 g (0.1 mol) of methyl 3-methyl-4-methoxyglyoxylate; the product ispurified by crystallization from petroleum ether/diethylether. Yield:11.1 g (33% of theory); melting point: 134° C.

[0121] I.9: ethyl 4,4′-dichlorobenzilate 3i

[0122] The product may be synthesized analogously to step I.5.

[0123] I.10: methyl 3,3′,5,5′-tetrafluorobenzilate 3j

[0124] I.10.1: 3,3′,5,5′-tetrafluorobenzil

[0125] 110 ml of ethanol are taken at ambient temperature and 50.0 g(0.352 mol) of 3,5-difluorobenzaldehyde and 444 g (0.018 mol) of3-ethyl-5-(2-hydroxyethyl)-4-methylthiazolium bromide is added. Then10.7 g (0.11 mol) of triethylamine is added dropwise. The mixture isrefluxed for 3 hours and evaporated to dryness. The residue is taken upin ethyl acetate and extracted with water, sodium pyrosulfite in water,and Na₂CO₃ solution. After drying over MgSO₄, the mixture is evaporatedto dryness. Yield: 39.91 g of yellow crystals (80% of theory).

[0126] 39.91 g of the acyloin thus obtained is dissolved in 1700 ml ofacetonitrile at ambient temperature, 0.2 ml ofvanadium-(V)-oxytrichloride is added, and oxygen is piped in. After 1.5hours, the solution is evaporated to dryness, extracted with ethylacetate and water, as well as Na₂CO₃ solution, dried over MgSO₄, andevaporated to dryness. The residue remaining is stirred with petroleumether/ethyl acetate 95:5. Yield: 26.61 g yellowish-green crystals (67%of theory); melting point: 136° C.-138° C.

[0127] I.10.2: 3,3′,5,5′-Tetrafluorobenzilic acid

[0128] 46.98 g (1.747 mol) of sodium hydroxide in 330 ml water areplaced in a boiling water bath with thorough stirring and a solution of26.61 g (0.094 mol) of 3,3′,5,5′-tetrafluorobenzil in 330 ml dioxane isadded dropwise and then stirred for another 1 hour. After cooling, thedioxane is evaporated; the residue is diluted with water and extractedwith diethylether. The organic phase is acidified, extracted withdichloromethane, dried over MgSO₄, evaporated to dryness. Yield: 20.15 gof yellowish crystals (71% of theory).

[0129] I.10.3: methyl 3,3′,5,5′-tetrafluorobenzilate:

[0130] 20.15 g (0.0671 mol) of 3,3′,5,5′-tetrafluorobenzilic acid areplaced in 250 ml acetonitrile, 18.6 g (0.121 mol) of DBU, and 34.4 g(0.2426 mol) of methyl iodide is added and then stirred for 6 hours atambient temperature. The reaction mixture is evaporated to dryness, theresidue extracted with ethyl acetate and water, the organic phase driedover MgSO₄, evaporated to dryness. The product is recrystallized fromcyclohexane. Yield: 15.11 g of beige crystals (68% of theory); meltingpoint: 113° C.-114° C.

[0131] I.11: methyl 3,3′-dichlorobenzilate 3k

[0132] I.11.1:3,3′-dichlorobenzil

[0133] 100 ml of ethanol are used at ambient temperature and 50.0 g(0.356 mol) of 3-chlorobenzaldehyde and 4.54 g (0.018 mol) of3-ethyl-5-(2-hydroxyethyl)-4-methylthiazolium bromide are added. Then10.7 g (0.11 mol) of triethylamine is added dropwise. The mixture isrefluxed for 3 hours and evaporated to dryness. The residue is taken upin ethyl acetate and extracted with water, sodium pyrosulfite in water,and Na₂CO₃ solution. After drying over MgSO₄, it is evaporated todryness. The product obtained is recrystallized from isopropanol andpetroleum ether. Yield: 13.2 g of white crystals (13% of theory);melting point: 69° C.-70° C.

[0134] 13.0 g of the acyloin thus obtained is dissolved in 460 mlacetonitrile at RT, 0.0867 g of vanadium-(V)-oxytrichloride is added andoxygen is piped in. After 1.5 hours, the solution is evaporated todryness, extracted with ethyl acetate and water, as well as Na₂CO₃solution, dried over MgSO₄, and evaporated to dryness. The residueremaining is stirred with petroleum ether/ethyl acetate 95:5. Yield:12.59 g of yellow crystals (97% of theory); melting point: 116° C.-117°C.

[0135] I.11.2: 3,3′-dichlorobenzilic acid

[0136] 51.45 g (1.286 mol) of sodium hydroxide in 1000 ml water areplaced in a bath of boiling water with thorough stirring and a solutionof 28.5 g (0.102 mol) of 3,3′-dichlorobenzil in 700 ml dioxane is addeddropwise and then stirred for another 1 hour. After cooling, the dioxaneis evaporated down, the residue is diluted with water and extracted withdiethylether. The organic phase is acidified, extracted withdichloromethane, dried over MgSO₄, evaporated to dryness. Yield: 32.7 g(71% of theory).

[0137] I.11.3: methyl 3,3′-dichlorobenzilate

[0138] From 100 ml of ethanol and 1.97 g (0.0855 mol) of sodium, asodium ethoxide solution is prepared to which 26.6 g (0.0855 mol) of3,3′-dichlorobenzilic acid in 50 ml of ethanol is added dropwise. Themixture is then stirred for 4 hours at ambient temperature. After thesolvent has been distilled off, the residue is dissolved in 150 ml DMFand 24.27 g (0.171 mol) of methyl iodide is added dropwise, then stirredfor another 24 hours. While cooling with ice, 300 ml of water and 200 mlof diethylether are added dropwise, the phases are separated, theaqueous phase is extracted with diethylether, then the organic phasesare washed with Na₂CO₃ solution and shaken with water till neutral.After drying over Na₂SO₄, the mixture is evaporated to dryness. Yield:22.91 g of yellow oil (82% of theory).

[0139] I.12: methyl 4,4′-di(trifluoromethyl)benzilate 3l

[0140] I.12.1: 4,4′-di(trifluoromethyl)benzil

[0141] The reaction to form the acyloin derivative is carried outanalogously to the process according to step I.11.1 starting from 174.1g of 4-(trifluoromethyl)benzaldehyde. Yield: 150.2 g of whitish-yellowcrystals (86% of theory).

[0142] 150.2 g of the acyloin thus obtained are reacted analogously tothe method according to step I.11.1 to obtain the benzil. Yield: 93.5 gof yellow crystals (63% of theory); melting point: 141° C.-142° C.

[0143] I.12.2: 4,4′-di(trifluoromethyl)benzilic acid

[0144] 10.00 g (0.0289 mol) of 4,4′-di(trifluoromethyl)benzil arereacted analogously to the method according to step I.11.2 to obtain thecorresponding benzilic acid. Yield: 8.15 g of yellowish crystals (77% oftheory).

[0145] I.12.3: methyl 4,4′-di(trifluoromethyl)benzilate

[0146] 38.5 g (0.115 mol) of 4,4′-di(trifluoromethyl)benzilic acid, 30.5g (0.20 mol) of DBU, and 56.8 g (0.40 mol) of methyl iodide are reactedin 400 ml acetonitrile analogously to step I.10.3. The product ispurified by flash chromatography (eluant cyclohexane/ethyl acetate95:5). Yield: 20.05 g of white crystals (46% of theory); melting point:68° C.

[0147] I.13: methyl 3,3′-di(trifluoromethyl)benzilate 3m

[0148] I.13.1: 3,3′-di(trifluoromethyl)benzil:

[0149] The reaction to form the acyloin derivative is carried outanalogously to the process according to step I.11.1 starting from 30.0 gof 3-(trifluoromethyl)benzaldehyde. Yield: 25.96 g of yellow oil (87% oftheory).

[0150] 25.96 g of the acyloin thus obtained are reacted analogously tothe method according to step I.11.1 to obtain the benzil. Yield: 10.5 gof light yellow crystals (24% of theory).

[0151] I.13.2: 3,3′-di(trifluoromethyl)benzilic acid

[0152] 10.5 g (0.0182 mol) of 3,3′-di(trifluoromethyl)benzil are reactedanalogously to the method according to step I.11.2 to obtain thecorresponding benzilic acid. Yield: 10.55 g of yellowish oil.

[0153] I.13.3: methyl 3,3′-di(trifluoromethyl)benzilate

[0154] 10.55 g (0.0289 mol) of 4,4′-di(trifluoromethyl)benzilic acid,8.82 g (0.0579 mol) of DBU, and 16.44 g (0.1158 mol) of methyl iodideare reacted in 110 ml acetonitrile analogously to step I.10.3. Theproduct is purified by recrystallization from cyclohexane. Yield: 6.02 gof white crystals (57% of theory); melting point: 69° C.-70° C.

[0155] I.14: methyl 3,3′-dichloro-4,4′-difluorobenzilate 3n

[0156] I.14.1: 3,3′-dichloro-4,4′-difluorobenzil

[0157] The reaction to form the acyloin derivative is carried outanalogously to the process according to step I.11.1 starting from 30.0 gof 3-chloro-4-fluorobenzaldehyde. Yield: 29.49 g of orange oil.

[0158] 29.49 g of the acyloin thus obtained are reacted analogously tothe method according to step I.11.1 to obtain the benzil. Yield: 24.88 gof yellow crystals.

[0159] I.14.2: 3,3′-dichloro-4,4′-difluorobenzilic acid

[0160] 24.88 g (0.079 mol) of 3,3′-dichloro-4,4′-difluorobenzil arereacted analogously to the method according to step I.11.2 to obtain thecorresponding benzilic acid. Yield: 17.07 g of orange solid.

[0161] I.14.3: methyl 3,3′-dichloro-4,4′-difluorobenzilate

[0162] 17.07 g (0.0512 mol) of 3,3′-dichloro-4,4′-difluorobenzilic acid,14.10 g (0.0926 mol) of DBU, and 26.29 g (0.1852 mol) of methyl iodideare reacted in 200 ml acetonitrile analogously to step I.10.3. Yield:6.77 g (38% of theory).

[0163] I.15: methyl 2,2′,5,5′-tetrafluorobenzilate 3o

[0164] I.15.1: 2,2′,5,5′-tetrafluorobenzil

[0165] The reaction to form the acyloin derivative is carried outanalogously to the process according to step I.11.1 starting from 50.0 g2,5-difluorobenzaldehyde. Yield: 45.5 g of yellow crystals.

[0166] 45.5 g of the acyloin thus obtained are reacted analogously tothe method according to step I.11.1 to obtain the benzil. Yield: 39.75 gof yellow crystals (88% of theory).

[0167] I.15.2: 2,2′,5,5′-tetrafluorobenzilic acid

[0168] 39.75 g (0.14 mol) of 2,2′,5,5′-tetrafluorobenzil are reactedanalogously to the method according to step I.11.2 to obtain thecorresponding benzilic acid. Yield: 44.76 g of yellowish oil.

[0169] I.15.3: methyl 2,2′,5,5′-tetrafluorobenzilate

[0170] 44.76 g (0.14 mol) of 2,2′,5,5′-tetrafluorobenzilbenzilic acidare reacted analogously to step I.10.3. Yield: 29.4 g of oil.

[0171] I.16: methyl 2,2′,3,3′-tetrafluorobenzilate 3p

[0172] I.16.1: 2,2′,3,3′-tetrafluorobenzil

[0173] The reaction to form the acyloin derivative is carried outanalogously to the process according to step I.11.1 starting from 30.0 g2,3-difluorobenzaldehyde. Yield: 29.85 g of yellow crystals.

[0174] 29.85 g of the acyloin thus obtained are reacted analogously tothe method according to step I.11.1 to obtain the benzil. Yield: 25.22 gof orange oil.

[0175] I.16.2: 2,2′,3,3′-tetrafluorobenzilic acid

[0176] 25.22 g (0.0894 mol) of 2,2′,3,3′-tetrafluorobenzil are reactedanalogously to the method according to step I.11.2 to obtain thecorresponding benzilic acid. Yield: 29.13 g of orange solid.

[0177] I.16.3: methyl 2,2′,3,3′-tetrafluorobenzilate

[0178] 29.13 g (0.097 mol) of 2,2′,3,3′-tetrafluorobenzilbenzilic acidare reacted analogously to step I.10.3. Yield: 15.78 g of beigecrystals; melting point: 102° C.-103° C.

[0179] I.17: methyl 3,3′-difluorobenzilate 3q

[0180] I.17.1: 3,3′-difluorobenzil

[0181] The reaction to form the acyloin derivative is carried outanalogously to the process according to step I.11.1 starting from 50.0 g3-fluorobenzaldehyde. Yield: 49.45 g.

[0182] 49.45 g of the acyloin thus obtained are reacted analogously tothe method according to step I.11.1 to obtain the benzil. Yield: 42.01 gof light yellow crystals; melting point: 104° C.-105° C.

[0183] I.17.2: 3,3′-difluorobenzilic acid

[0184] 42.01 g (0.171 mol) of 3,3′-difluorobenzil are reactedanalogously to the method according to step I.11.2 to obtain thecorresponding benzilic acid. Yield: 33.07 g (75% of theory); meltingpoint: 121° C.-122° C.

[0185] I.17.3: methyl 3,3′-difluorobenzilate

[0186] 33.7 g (0.128 mol) of 3,3′-difluorobenzilbenzilic acid arereacted analogously to step I.10.3. Yield: 34.78 g beige crystals (98%of theory); melting point: 84° C.-85° C.

[0187] I.18: methyl 4,4′-dichloro-3,3′-difluorobenzilate 3r

[0188] I.18.1: 4,4′-dichloro-3,3′-difluorobenzil

[0189] The reaction to form the acyloin derivative is carried outanalogously to the process according to step I.11.1 starting from 33.13g 4-chloro-3-fluorobenzaldehyde. Yield: 30.07 g of oil.

[0190] 30.07 g of the acyloin thus obtained are reacted analogously tothe method according to step I.11.1 to obtain the benzil. Yield: 19.32 gof light yellow powder.

[0191] I.18.2: 4,4′-dichloro-3,3′-difluorobenzilic acid

[0192] 19.32 g (0.0613 mol) of 4,4′-dichloro-3,3′-difluorobenzil arereacted analogously to the method according to step I.11.2 to obtain thecorresponding benzilic acid. Yield: 25.3 g of oil.

[0193] I.18.3: methyl 4,4′-dichloro-3,3′-difluorobenzilate

[0194] 25.3 g (0.075 mol) of 4,4′-dichloro-3,3′-difluorobenzilic acidare reacted analogously to step I.10.3. Yield: 13.07 g of yellow oil(50% of theory).

[0195] I.19: methyl 3,3′,4,4′-tetrachlorobenzilate 3s

[0196] I.19.1: 3,3′,4,4′-tetrachlorobenzil

[0197] The reaction to form the acyloin derivative is carried outanalogously to the process according to step I.11.1 starting from 100 gof 3,4-dichlorobenzaldehyde. Yield: 60.89 g of oil.

[0198] 60.89 g of the acyloin thus obtained are reacted analogously tothe method according to step I.11.1 to obtain the benzil. Yield: 42.45 gof yellow crystals.

[0199] I.19.2: 3,3′,4,4′-tetrachlorobenzilic acid

[0200] 44.75 g (0.128 mol) of 3,3′,4,4′-tetrachlorobenzil are reactedanalogously to the method according to step I.11.2 to obtain thecorresponding benzilic acid. Yield: 42 g of yellowish powder; meltingpoint: 224° C.

[0201] I.19.3: methyl 3,3′,4,4′-tetrachlorobenzilate

[0202] 42 g (0.114 mol) of 3,3′,4,4′-tetrachlorobenzilic acid arereacted analogously to step I.10.3. Yield: 15.84 g (37% of theory);melting point: 69° C.

[0203] I.20: methyl 3,3′,4,4′,5,5′-hexafluorobenzilate 3t

[0204] I.20.1: 3,3′,4,4′,5,5′-hexafluorobenzil

[0205] The reaction to form the acyloin derivative is carried outanalogously to the process according to step I.11.1 starting from 31.38g of 3,4,5-trifluorobenzaldehyde. Yield: 24.92 g.

[0206] 24.92 g of the acyloin thus obtained are reacted analogously tothe method according to step I.11.1 to obtain the benzil. Yield: 14.65 gof yellow crystals.

[0207] I.20.2: 3,3′,4,4′,5,5′-hexafluorobenzilic acid

[0208] 14,62 g (0.046 mol) of 3,3′,4,4′,5,5′-hexafluorobenzil arereacted analogously to the method according to step I.11.2 to obtain thecorresponding benzilic acid. Yield: 15.77 g of yellow crystals.

[0209] I.20.3: methyl 3,3′,4,4′,5,5′-hexafluorobenzilbenzilate

[0210] 42 g (0.114 mol) of 3,3′,4,4′-tetrachlorobenzilic acid arereacted analogously to step I.10.3. Yield: 5.65 g (35% of theory);melting point: 82° C.-83° C.

[0211] II. Synthesis of the Compounds of General Formula 4

[0212] II.1: tropenol 3,3′,4,4′-tetrafluorobenzilate 4.1

[0213] 4.27 g (0.013 mol) of ethyl 3,3′,4,4′-tetrafluorobenzilate 3a,1.81 g (0.013 mol) of tropenol, and 0.03 g of sodium are heated for 4hours as a melt at 75 mbar over a bath of boiling water with occasionalshaking. After cooling, the sodium residues are dissolved withacetonitrile, the solution is evaporated to dryness and the residue isextracted with dichloromethane/water. The organic phase is washed withwater, dried over MgSO₄, and evaporated to dryness. The residueremaining is combined with diethylether/petroleum ether (1:9), suctionfiltered, and washed. Yield: 2.50 g (46% of theory); TLC: R_(f) value:0.29 (eluant: sec-butanol/formic acid/water 75:15:10); melting point:147° C.-148° C.

[0214] II.2: scopine 3,3′,4,4′-tetrafluorobenzilate 4.2

[0215] 4.2 is prepared analogously to the method according to II.1.Yield: 1.75 g (36% of theory) starting from 3.61 g (0.011 mol) of 3a and1.71 g (0.011 mol) of scopine; TLC: R_(f) value: 0.22 (eluant as in stepII.1); melting point: 178° C.-179° C.

[0216] II.3: tropenol 4,4′-dichlorobenzilate 4.3

[0217] 4.3 is prepared analogously to the method according to II.1.Yield: 6.95 g (83% of theory) starting from 6.5 g (0.02 mol) of 3i and2.78 g (0.02 mol) of tropenol; TLC: R_(f) value: 0.30 (eluant as in stepII.1); melting point: 197° C.-199° C.

[0218] II.4: tropenol 2,2′-dichlorobenzilate 4.4

[0219] 4.4 is prepared analogously to the method according to II.1; theproduct was precipitated as the hydrochloride and recrystallized fromacetonitrile. Yield: 1.13 g (8% of theory) starting from 9.3 g (0.03mol) of 3b and 8.32 g (0.06 mol) of tropenol; TLC: R_(f) value: 0.26(eluant as in step II.1); melting point: 253° C.-256° C.(hydrochloride).

[0220] II.5: tropenol 4,4′-difluorobenzilate 4.5

[0221] 4.5 is prepared analogously to the method according to II.1.Yield: 8.71 g (69% of theory) starting from 8.35 g (0.03 mol) of 3c and4.18 g (0.03 mol) of tropenol; TLC: R_(f) value: 0.34 (eluant as in stepII.1); melting point: 167° C.-169° C.

[0222] II.6: tropenol 2,2′,4,4′-tetrafluorobenzilate 4.6:

[0223] 4.6 is prepared analogously to the method according to II.1.Yield: 1.80 g (27% of theory) starting from 4.00 g (0.013 mol) of 3d and3.54 g (0.036 mol) of tropenol; melting point: 190° C.

[0224] II.7: scopine 4,4′-dichlorobenzilate 4.7

[0225] 3.78 g (0.01 mol) of tropenol 4,4′-dichlorobenzilate 4.3 aresuspended in 40 ml of DMF and heated to 60° C. until a clear solution isformed. At an internal temperature of about 40° C., a solution of 1.92 g(0.0216 mol) of H₂O₂-urea in 10 ml of water, and 0.183 g (0.0011 mol) ofvanadium-(V)-oxide is added and the mixture is stirred for 4.5 hours at60° C. After cooling to 20° C., the precipitate formed is suctionfiltered, the filtrate is adjusted to pH 3 with 4 N hydrochloric acidand combined with 0.437 g (0.0023 mol) of Na₂S₂O₇ in 10 ml of water. Thegreen solution thus formed is evaporated to dryness, the residue isextracted with dichloromethane/water. The acidic aqueous phase is madebasic with Na₂CO₃, extracted with dichloromethane, and the organic phaseis dried over Na₂SO₄ and concentrated. Then 0.5 ml of acetyl chloride isadded at about 15° C. and the mixture is stirred for 1.5 hours. Afterextraction with 0.1 N hydrochloric acid, the aqueous phase is madebasic, extracted with dichloromethane; the organic phase is dried overNa₂SO₄ and evaporated to dryness. The hydrochloride is precipitated fromthe residue and recrystallized from methanol/diethylether. Yield: 1.92 gof 18 (45% of theory); TLC: R_(f) value: 0.29 (eluant as in II.1);melting point: 238° C.-239° C. (hydrochloride).

[0226] II.8: scopine 4,4′-difluorobenzilate 4.8

[0227] 4.8 is prepared analogously to the method according to II.7.Yield: 2.60 g (70% of theory) starting from 3.27 g (0.09 mol) of 4e;TLC: R_(f) value: 0.25 (eluant as in step II.1); melting point: 243°C.-244° C. (hydrochloride).

[0228] II.9: tropenol 4,4′-dibromobenzilate 4.9

[0229] 4.9 is prepared analogously to the method according to II.1.Yield: 2.36 g (19% of theory) starting from 9.9 g (0.023 mol) ofcommercially obtainable isopropyl 4,4′-dibromobenzilate and 3.21 g(0.023 mol) of tropenol; to purify it, the hydrochloride wasprecipitated and recrystallized from acetonitrile. TLC: R_(f) value:0.30 (eluant as in step II.1); melting point: 205° C.-207° C.(hydrochloride).

[0230] II.10: tropenol 4,4′-dimethylbenzilate 4.10

[0231] 4.10 is prepared analogously to the method according to II.1.Yield: 3.55 g (81% of theory) starting from 2.87 g (0.01 mol) of 3e and1.48 g (0.01 mol) of tropenol; to purify it, the hydrochloride wasprecipitated and recrystallized from acetonitrile. Melting point: 232°C.-233° C. (hydrochloride).

[0232] II.11: scopine 4,4′-dimethylbenzilate 4.11

[0233] 4.11 is prepared analogously to the method according to II.1.Yield: 1.02 g (24% of theory) starting from 2.87 g (0.01 mol) of 3e and1.65 g (0.01 mol) of scopine; to purify it, the hydrochloride wasprecipitated. Melting point: 181° C.-183° C. (hydrochloride).

[0234] II.12: tropine 3,3′,4,4′-tetrafluorobenzilate 4.12

[0235] 4.12 is prepared analogously to the method according to II.1.Yield: 2.35 g (53% of theory) starting from 3.45 g (0.01 mol) of 3a and1.49 g (0.01 mol) of tropine; melting point: 142° C.-144° C.

[0236] II.13: tropenol 3,3′,4,4′-tetramethoxybenzilate 4.13

[0237] 2.60 g (0.007 mol) of 3f, 1.00 g (0.007 mol) of tropenol and 0.03g of sodium are placed in 15 ml of toluene and refluxed for 4 hours.After cooling, the mixture is diluted with about 100 ml of toluene andextracted with water; the organic phase is dried over MgSO₄ andevaporated to dryness. Yield: 1.60 g of oil (47% of theory).

[0238] II.14: tropenol 4,4′-dimethoxybenzilate 4.14

[0239] 4.14 is prepared analogously to the method according to II.1.Yield: 3.3 g (78% of theory) starting from 3.0 g (0.01 mol) of 3g and1.39 g (0.01 mol) of tropenol; melting point: 146° C.-147° C.

[0240] II.15: tropine 3,3′,4,4′-tetramethoxybenzilate 4.15

[0241] 4.15 is prepared analogously to the method according to II.1.Yield: 1.65 g (32% of theory; oil) starting from 4.0 g (0.02 mol) of 3fand 3.12 g (0.02 mol) of tropine.

[0242] II.16: scopine 3,3′,4,4′-tetramethoxybenzilate 4.16

[0243] 4.16 is prepared analogously to the method according to II.7.Yield: 0.8 g (41% of theory, oil) starting from 1.857 g (0.004 mol) of4.13.

[0244] II.17: tropenol 3,3′-dimethyl-4,4′-dimethoxvbenzilate 4.17

[0245] 4.17 is prepared analogously to the method according to II.1; theproduct is purified by recrystallizing from diethylether. Yield: 2.30 g(35% of theory) starting from 5.0 g (0.015 mol) of 3h and 4.21 g (0.03mol) of tropenol; melting point: 126° C.

[0246] II.18: scopine 3,3′-dimethyl-4,4′-dimethoxybenzilate 4.18

[0247] 4.18 is prepared analogously to the method according to II.7.Yield: 0.6 g (44% of theory, oil) starting from 1.3 g (0.003 mol) of 4q.

[0248] II.19: tropenol 3,3′,5,5′-tetrafluorobenzilate 4.19

[0249] 1.53 g (0.0636 mol) of NaH are placed in 30 ml of toluene, asolution of 14 g (0.0446 mol) of 3j and 8.85 g (0.0636 mol) of tropenolin 80 ml of toluene is added dropwise at 10° C. and 860 mbar. Thealcohol produced during the reaction is distilled off while at the sametime toluene is added dropwise. After 3 hours, the mixture is cooled andextracted, with dichloromethane and water. The combined organic phaseswere dried over MgSO₄ and evaporated to dryness. The residue was stirredwith petroleum ether/ethyl acetate 95:5. Yield: 11.21 g of light beigecrystals (60% of theory); melting point: 168° C.-170° C.

[0250] II.20: scopine 2,2′,4,4′-tetrafluorobenzilate 4.20

[0251] The preparation of 4.20 is carried out analogously to the processaccording to II.7. Yield: 1.05 g of white crystals (89% of theory)starting from 1.15 g (0.0027 mol) of 4.6.

[0252] II.21: scopine 3,3′,5,5′-tetrafluorobenzilate 4.21

[0253] The preparation of 4.21 is carried out analogously to the processaccording to II.7. Yield: 1.13 g of white crystals (55% of theory)starting from 2.0 g (0.0047 mol) of 4.19; melting point: 199° C.-200° C.

[0254] II.22: tropenol 3,3′-dichlorobenzilate 4.22

[0255] 22.9 g (0.074 mol) of methyl 3,3′-dichlorobenzilate 3k, 15.37 g(0.11 mol) of tropenol, and 0.17 g of sodium are heated for 4 hours as amelt over a bath of boiling water at 75 mbar with occasional shaking.After cooling, the sodium residues are dissolved with acetonitrile, thesolution is evaporated to dryness and the residue is extracted withdichloromethane/water. The organic phase is washed with water, driedover MgSO₄, and evaporated to dryness. The product is recrystallizedfrom acetonitrile in the form of its hydrochloride. Yield: 16.83 g ofwhite crystals (50% of theory); melting point: 184° C.-185° C.

[0256] II.23: tropenol 4,4′-di(trifluoromethyl)benzilate 4.23

[0257] Starting from 10.0 g (0.0264 mol) of 31 the reaction is carriedout analogously to step I.1. Yield: 4.70 g of beige crystals (37% oftheory); melting point: 155° C.

[0258] II.24: tropenol 3,3′-di(trifluoromethyl)benzilate 4.24

[0259] Starting from 6.01 g (0.0159 mol) of 3m the reaction is carriedout analogously to step II.1. Yield: 3.03 g of white crystals (39% oftheory); melting point: 124° C.-125° C.

[0260] II.25: scopine 4,4′-di(trifluoromethyl)benzilate 4.25

[0261] The preparation of 4.25 is carried out analogously to the processaccording to I.7. Yield: 0.95 g of clear oil (46% of theory) startingfrom 2.0 g (0.0041 mol) of 4.23.

[0262] II.26: scopine 3,3′-di(trifluoromethyl)benzilate 4.26

[0263] The preparation of 4.26 is carried out analogously to the processaccording to I.7. Yield: 1.02 g of white crystals (51% of theory)starting from 1.94 g (0.0039 mol) of 4.24.

[0264] II.27: tropenol 3,3′-dichloro-4,4′-difluorobenzilate 4.27

[0265] Starting from 6.77 g (0.0195 mol) of 3n the reaction is carriedout analogously to step II.1. The crude product obtained isrecrystallized from acetonitrile. Yield: 4.05 g of light beige crystals(46% of theory); melting point: 177° C.-179° C.

[0266] II.28: scopine 3,3′-dichlorobenzilate 4.28

[0267] The preparation of 4.28 is carried out analogously to the processaccording to I.7. Yield: 7.86 g (75% of theory) starting from 10.37 g(0.024 mol) of 4.22; melting point: 174° C.-175° C.

[0268] II.29: tropenol 2,2′,5,5′-tetrafluorobenzilate 4.29

[0269] Starting from 6.29 g (0.02 mol) of 3o the reaction is carried outanalogously to step II.1. The crude product obtained is recrystallizedfrom acetone in the form of the hydrochloride. Yield: 0.89 g of whitecrystals (10% of theory); melting point: 177° C.-179° C.

[0270] II.30: tropenol 2,2′,3,3′-tetrafluorobenzilate 4.30

[0271] Starting from 8.0 g (0.0255 mol) of 3p the reaction is carriedout analogously to step II.1. The crude product obtained isrecrystallized from acetonitrile. Yield: 0.96 g of beige crystals (9% oftheory); melting point: 176° C.-177° C.

[0272] II.31: tropenol 3,3′-difluorobenzilate 4.31

[0273] Starting from 11.13 g (0.04 mol) of 3q the reaction is carriedout analogously to step II.1. The crude product obtained isrecrystallized from acetonitrile in the form of the hydrochloride.Yield: 7.98 g (47% of theory); melting point: 245° C.-246° C.

[0274] II.32: scopine 3,3′-difluorobenzilate 4.32

[0275] The preparation of 4.32 is carried out analogously to the processaccording to II.7. Yield: 4.2 g (76% of theory) starting from 4.89 g(0.013 mol) of 4.31; melting point: 216° C.-218° C.

[0276] II.33: scopine 3,3′-dichloro-4,4′-difluorobenzilate 4.33

[0277] The preparation of 4.33 is carried out analogously to the processaccording to II.7. Yield: 0.78 g of white crystals (34% of theory)starting from 4.6 g (0.0098 mol) of 4.27; melting point: 216° C.-218° C.

[0278] II.34: tropenol 4,4′-dichloro-3,3′-difluorobenzilate 4.34

[0279] Starting from 12.0 g (0.0345 mol) of 3r the reaction is carriedout analogously to step II.1. The crude product obtained is extractedfrom petroleum ether. Yield: 6.65 g of creamy-white powder (42% oftheory); melting point: 180° C.-181° C.

[0280] II.35: scopine 4,4′-dichloro-3,3′-difluorobenzilate 4.35

[0281] The preparation of 4.35 is carried out analogously to the processaccording to I.7. Yield: 2.58 g of white crystals (62% of theory)starting from 4.0 g (0.0088 mol) of 4.34; melting point: 150° C.-151° C.

[0282] II.36: tropenol 3,3′,4,4′-tetrachlorobenzilate 4.36

[0283] Starting from 14.24 g (0.0375 mol) of 3s the reaction is carriedout analogously to step II.1. The crude product obtained isrecrystallized from acetonitrile. Yield: 4.81 g of white crystals (26%of theory); melting point: 149° C.-150° C.

[0284] II.37: tropenol 3,3′,4,4′,5,5′-hexafluorobenzilate 4.37

[0285] Starting from 5.0 g (0.0143 mol) of 3t the reaction is carriedout analogously to step II.1. The crude product obtained isrecrystallized from acetonitrile. Yield: 3.49 g of white crystals (53%of theory); melting point: 164° C.-165° C.

[0286] III. Synthesis of the Compounds of General Formula 1

EXAMPLE 1 Tropenol 3,3′,4,4′-tetrafluorobenzilate methobromide

[0287]

[0288] 2.00 g (0.0048 mol) of 4.1, 30 ml of acetonitrile, 10 ml ofdichloromethane, and 2.88 g (0.0143 mol) of 46.92% bromomethane inacetonitrile are combined at 20° C. and left to stand for 3 days. Thesolution is evaporated to dryness and the residue is recrystallized fromacetonitrile. Yield: 1.95 g (80% of theory); TLC: R_(f) value: 0.12(eluant as in step II.1); melting point: 238° C.; C₂₃H₂₂F₄NO₃xBr(516.33); Elemental analysis: calculated: C (53.50) H (4.29) N (2.71)found: C (53.52) H (4.30) N (2.65).

EXAMPLE 2 Scopine 3,3′,4,4′-tetrafluorobenzilate methobromide

[0289]

[0290] 1.5 g (0.0034 mol) of 4.2, 20 ml of acetonitrile, 20 ml ofdichloromethane, and 2.08 g (0.01 mol) of 46.92% bromomethane inacetonitrile are reacted analogously to Example 1. Yield: 1.40 g (77% oftheory); TLC: R_(f) value: 0.16 (eluant as in step II.1); melting point:227° C.; C₂₃H₂₂F₄NO₄xBr (532.33). Elemental analysis: calculated: C(51.90) H (4.17) N (2.63) found: C (51.91) H (4.16) N (2.60).

EXAMPLE 3 Tropenol 4,4′-dichlorobenzilate methobromide

[0291]

[0292] 2.09 g (0.005 mol) of 4.3 are reacted analogously to Example 1.The crystals formed are suction filtered, washed with dichloromethane,dried, and then recrystallized from methanol/diethylether. Yield: 1.72 g(67% of theory); TLC: R_(f) value: 0.12 (eluant as in step II.1);melting point: 195° C.-196° C.; C₂₃H₂₄Cl₂NO₃xBr (513.26). Elementalanalysis: calculated: C (53.82) H (4.71) N (2.73) found: C (53.54) H(4.80) N (2.73).

EXAMPLE 4 Tropenol 2,2′-dichlorobenzilate methobromide

[0293]

[0294] 0.86 g (0.0021 mol) of the free base of 4.4 are reactedanalogously to Example 1. The crystals formed are suction filtered,washed with acetone, dried, and then recrystallized frommethanol/diethylether. Yield: 0.99 g (94% of theory); TLC: R_(f) value:0.14 (eluant as in step II.1); melting point: 260° C.-261° C.;C₂₃H₂₄Cl₂NO₃xBr (513.26). Elemental analysis: calculated: C (53.82) H(4.71) N (2.73) found: C (53.62) H (4.76) N (2.69).

EXAMPLE 5 Tropenol 4,4′-difluorobenzilate methobromide

[0295]

[0296] 1.9 g (0.005 mol) of the free base of 4.5 are reacted analogouslyto Example 1. Yield: 2.1 g (89% of theory); TLC: R_(f) value: 0.14(eluant as in step II.1); melting point: 219° C.-220° C.; C₂₃H₂₄F₂NO₃xBr(480.35). Elemental analysis: calculated: C (57.51) H (5.04) N (2.92)found: C (57.33) H (4.86) N (2.90).

EXAMPLE 6 Tropenol 2,2′,4,4′-tetrafluorobenzilate methobromide

[0297]

[0298] 1.60 g (0.004 mol) of 4.6 are reacted analogously to Example 1.The crystals formed are suction filtered and recrystallized fromacetone. Yield: 1.70 g (87% of theory); TLC: R_(f) value: 0.13 (eluant:n-butanol/water/formic acid (conc.)/acetone/dichloromethane36:15:15:15:5); melting point: 241° C.-242° C.; C₂₃H₂₂F₄NO₃xBr (516.33).Elemental analysis: calculated: C (53.50) H (4.29) N (2.71) found: C(53.55) H (4.33) N (2.73).

EXAMPLE 7 Scopine 4,4′-dichlorobenzilate methobromide

[0299]

[0300] 1.54 g (0.0035 mol) of the free base of 4.7 are reactedanalogously to Example 1. The crystals formed are suction filtered,washed with acetone, dried, and then recrystallized frommethanol/diethylether. Yield: 1.68 g (90% of theory); TLC: R_(f) value:0.22 (eluant as in step II.1); melting point: 209° C.-210° C.;C₂₃H₂₄Cl₂NO₄xBr (529.26). Elemental analysis: calculated: C (52.20) H(4.57) N (2.65) found: C (51.25) H (4.83) N (2.49).

EXAMPLE 8 Scopine 4,4′-difluorobenzilate methobromide

[0301]

[0302] 1.50 g (0.003 mol) of the free base of 4.8 are reactedanalogously to Example 1. The crystals formed are suction filtered,washed with acetone, dried, and then recrystallized frommethanol/diethylether. Yield: 1.73 g (93% of theory); TLC: R_(f) value:0.19 (eluant as in step II.1); melting point: 224° C.-225° C.;C₂₃H₂₄F₂NO₄xBr (496.35). Elemental analysis: calculated: C (55.66) H(4.87) N (2.82) found: C (55.20) H (4.81) N (2.82).

EXAMPLE 9 Tropenol 2,2′,4,4′-tetrafluorobenzilate methobromide

[0303]

[0304] 1.50 g (0.003 mol) of the free base of 4.9 are reactedanalogously to Example 1. The crystals formed are recrystallized frommethanol. Yield: 1.53 g (86% of theory); TLC: R_(f) value: 0.14 (eluantas in step II.1); melting point: 175° C.-177° C.; C₂₃H₂₄Br₂NO₃xBr(602.16). Elemental analysis: calculated: C (45.88) H (4.02) N (2.33)found: C (45.46) H (4.42) N (2.18).

EXAMPLE 10 Tropenol 4,4′-dimethylbenzilate methobromide

[0305]

[0306] 2.60 g (0.007 mol) of the free base of 4.10 are reactedanalogously to Example 1. The crystals formed are recrystallized fromethanol. Yield: 3.16 g (97% of theory); TLC: R_(f) value: 0.14 (eluantas in step II.1); C₂₅H₃₀NO₃xBr (472.42). Elemental analysis: calculated:C (63.56) H (6.40) N (2.96) found: C (62.88) H (6.87) N (2.74).

EXAMPLE 11 Scopine 4,4′-dimethylbenzilate methobromide

[0307]

[0308] 0.56 g (0.0014 mol) of the free base of 4.11 are reactedanalogously to Example 1. The crystals formed are recrystallized frommethanol/diethylether. Yield: 0.55 g (80% of theory); TLC: R_(f) value:0.19 (eluant as in step II.1); melting point: 221° C.-222° C.;C₂₅H₃₀NO₄xBr (488.42). Elemental analysis: calculated: C (61.48) H(6.19) N (2.87) found: C (60.61) H (6.31) N (2.80).

EXAMPLE 12 Tropine 3,340 ,4,4′-tetrafluorobenzilate methobromide

[0309]

[0310] 1.80 g (0.004 mol) of the free base of 4.12 are reactedanalogously to Example 1. Yield: 1.73 g (78% of theory); TLC: R_(f)value: 0.10 (eluant as in step II.1); melting point: 157° C.;C₂₃H₂₄F₄NO₃xBr (518.34). Elemental analysis: calculated: C (53.30) H(4.67) N (2.70) found: C (53.39) H (4.53) N (2.73).

EXAMPLE 13 Tropenol 3,3′,4,4′-tetramethoxybenzilate methobromide

[0311]

[0312] 1.20 g (0.003 mol) of 4.13 are reacted analogously to Example 1.The crystals formed are recrystallized from acetonitrile/diethylether.Yield: 1.05 g (73% of theory); TLC: R_(f) value: 0.10 (eluant as in stepII.1); melting point: 212° C.; C₂₇H₃₄NO₇xBr (564.47); Elementalanalysis: calculated: C (57.45) H (6.07) N (2.48) found: C (56.91) H(6.05) N (2.45).

EXAMPLE 14 Tropenol 4,4′-dimethoxybenzilate methobromide

[0313]

[0314] 1.13 g (0.003 mol) of 4.14 are reacted analogously to Example 1.The crystals formed are recrystallized from acetonitrile/diethylether.Yield: 1.21 g (87% of theory); C₂₅H₃₀NO₅xBr (504.42); TLC: R_(f) value:0.01 (eluant as in step II.1); melting point: 180° C.-181° C. Elementalanalysis: calculated: C (59.53) H (5.99) N (2.78) found: C (59.29) H(6.24) N (2.84).

EXAMPLE 15 Tropine 3,3′,4,4′-tetramethoxybenzilate methobromide

[0315]

[0316] 1.65 g (0.004 mol) of 4.15 are reacted analogously to Example 1.The crystals formed are recrystallized from diethylether. Yield: 1.70 g(86% of theory); melting point: 148° C.-150° C.; C₂₇H₃₆NO₇xBr (566.49).Elemental analysis: calculated: C (57.25) H (6.41) N (2.47) found: C(56.41) H (6.75) N (2.45).

EXAMPLE 16 Scopine 3,3′,4,4′-tetramethoxybenzilate methobromide

[0317]

[0318] 0.80 g (0.0017 mol) of 4.16 are reacted analogously to Example 1.The crystals formed are recrystallized from acetone. Yield: 0.35 g (37%of theory); melting point: 211° C.-212° C.; C₂₇H₃₄NO₈xBr (580.47).Elemental analysis: calculated: C (55.87) H (5.90) N (2.41) found: C(55.62) H (6.09) N (2.53).

EXAMPLE 17 Tropenol 3,3′-dimethyl-4,4′-dimethoxybenzilate methobromide

[0319]

[0320] 1.00 g (0.003 mol) of 4.17 are reacted analogously to Example 1.Yield: 0.85 g (70% of theory); melting point: 217° C.; C₂₇H₃₄NO₅xBr(532.47). Elemental analysis: calculated: C (60.90) H (6.51) N (2.63)found: C (59.83) H (6.51) N (2.93).

EXAMPLE 18 Scopine 3,3′-dimethyl-4,4′-dimethoxybenzilate

[0321]

[0322] 0.60 g (0.0013 mol) of 4.18 are reacted analogously to Example 1.The product is purified by crystallization from acetone. Yield: 0.40 g(56% of theory); C₂₇H₃₄NO₆xBr (548.47). Elemental analysis: calculated:C (59.13) H (6.25) N (2.55) found: C (58.69) H (6.54) N (2.61).

EXAMPLE 19 Tropenol 3,3′,4,4′-tetrafluorobenzilate ethylbromide

[0323]

[0324] 2.00 g (0.0048 mol) of 4.1 is dissolved in 20 ml dichloromethaneand 20 ml acetonitrile, combined with 2.59 g (0.0238 mol) of bromoethaneand the reaction vessel is sealed. It is left to stand at about 20° C.for 3 weeks with the exclusion of light. The solution is evaporated todryness and the residue is recrystallized from acetonitrile. Yield: 1.96g of 3 (78% of theory); TLC: R_(f) value: 0.11 (eluant as in step II.1);melting point: 247° C. Elemental analysis: calculated: C (54.35) H(4.56) N (2.64) found: C (53.93) H (4.59) N (2.60).

EXAMPLE 20 Tropenol 3,3′,5,5′-tetrafluorobenzilate methobromide

[0325]

[0326] 2.0 g (0.0047 mol) of 4.19 are reacted analogously to Example 1.Yield: 2.22 g of white crystals (92% of theory); melting point: 262°C.-264° C.; C₂₃H₂₂F₄NO₃xBr (516.33). Elemental analysis: calculated: C(53.50) H (4.29) N (2.71) found: C (53.48) H (4.30) N (2.65).

EXAMPLE 21 Scopine 2,2′,4,4′-tetrafluorobenzilate methobromide

[0327]

[0328] 1.05 g (0.0024 mol) of 4.20 are reacted analogously to Example 1.Yield: 0.54 g of white crystals (42% of theory); melting point: 208°C.-209° C.; C₂₃H₂₂F₄NO₄xBr (532.33). Elemental analysis: calculated: C(51.90) H (4.17) N (2.63) found: C (50.84) H (4.39) N (2.50).

EXAMPLE 22 Scopine 3,3′,5,5′-tetrafluorobenzilate methobromide

[0329]

[0330] 1.13 g (0.00258 mol) of 4.21 are reacted analogously toExample 1. Yield: 1.07 g of white crystals (78% of theory); meltingpoint: 238° C.-239° C.; C₂₃H₂₂F₄NO₄xBr (532.33). Elemental analysis:calculated: C (51.90) H (4.17) N (2.63) found: C (51.85) H (4.29) N(2.70).

EXAMPLE 23 Tropenol 3,3′-dichlorobenzilate methobromide

[0331]

[0332] 2.09 g (0.005 mol) of 4.22 are reacted analogously to Example 1.Yield: 2.42 g of white crystals (94% of theory); melting point: 200°C.-201° C.; C₂₃H₂₄Cl₂NO₃xBr (513.26). Elemental analysis: calculated: C(53.82) H (4.71) N (2.73) found: C (53.73) H (4.74) N (2.78).

EXAMPLE 24 Tropenol 4,4′-di(trifluoromethyl)benzilate methobromide

[0333]

[0334] 1.2 g (0.00247 mol) of 4.23 are reacted analogously to Example 1.Yield: 1.05 g of white crystals (73% of theory); melting point: 140°C.-141° C.; C₂₅H₂₄F₆NO₃xBr (580.36).

EXAMPLE 25 Tropenol 3,3′-di(trifluoromethyl)benzilate methobromide

[0335]

[0336] 1.09 g (0.00225 mol) of 4.24 are reacted analogously toExample 1. Yield: 0.84 g of white crystals (65% of theory); meltingpoint: 228° C.-229° C.; C₂₅H₂₄F₆NO₃xBr (580.36). Elemental analysis:calculated: C (51.74) H (4.17) N (2.41) found: C (51.40) H (4.24) N(2.42).

EXAMPLE 26 Scopine 4,4′-di(trifluoromethyl)benzilate methobromide

[0337]

[0338] 0.95 g (0.0019 mol) of 4.25 are reacted analogously to Example 1.The product is recrystallized from diethylether. Yield: 0.98 g of whitecrystals (87% of theory); melting point: 158° C.-160° C.; C₂₅H₂₄F₆NO₄xBr(596.36). Elemental analysis: calculated: C (50.35) H (4.06) N (2.35)found: C (50.34) H (4.03) N (2.36).

EXAMPLE 27 Scopine 3,3′-di(trifluoromethyl)benzilate methobromide

[0339]

[0340] 1.0 g (0.002 mol) of 4.26 are reacted analogously to Example 1.The product is recrystallized from acetonitrile. Yield: 0.7 g of whitecrystals (59% of theory); melting point: 220° C.-221° C.; C₂₅H₂₄F₆NO₄xBr(596.36). Elemental analysis: calculated: C (50.35) H (4.06) N (2.35)found: C (50.24) H (4.17) N (2.40).

EXAMPLE 28 Tropenol 4,4′-difluorobenzilate ethyl bromide

[0341]

[0342] 1.54 g (0.004 mol) of 4.5 are reacted analogously to Example 19.The product is recrystallized from ethanol. Yield: 1.72 g of whitecrystals (87% of theory); melting point: 228° C.-229° C.; C₂₄H₂₆F₂NO₃xBr(494.37). Elemental analysis: calculated: C (58.31) H (5.30) N (2.83)found: C (58.25) H (5.29) N (2.83).

EXAMPLE 29 Tropenol 3,3′-dichloro-4,4′-difluorobenzilate methobromide

[0343]

[0344] 1.5 g (0.0033 mol) of 4.27 are reacted analogously to Example 1.The product is recrystallized from acetonitrile. Yield: 1.49 g of whitecrystals (82% of theory); melting point: 245° C.-246° C.;C₂₃H₂₂Cl₂F₂NO₃xBr (549.24). Elemental analysis: calculated: C (50.30) H(4.04) N (2.55) found: C (50.44) H (4.19) N (2.51).

EXAMPLE 30 Scopine 3,3′-dichlorobenzilate methobromide

[0345]

[0346] 2.61 g (0.006 mol) of 4.28 are reacted analogously to Example 1.The product is recrystallized from ethanol. Yield: 2.13 g of whitecrystals (67% of theory); melting point: 221° C.-222° C.;C₂₃H₂₄Cl₂NO₄xBr (529.26). Elemental analysis: calculated: C (52.20) H(4.57) N (2.65) found: C (52.25) H (4.61) N (2.70).

EXAMPLE 31 2, tropenol 2′,5,5′-tetrafluorobenzilate methobromide

[0347]

[0348] 0.67 g (0.0016 mol) of 4.29 are reacted analogously to Example 1.The product is recrystallized from methanol/diethylether. Yield: 0.70 gof white crystals (86% of theory); melting point: 269° C.-270° C.;C₂₃H₂₂F₄NO₃xBr (516.33). Elemental analysis: calculated: C (53.50) H(4.29) N (2.71) found: C (53.30) H (4.52) N (2.76).

EXAMPLE 32 2, tropenol 2′,3,3′-tetrafluorobenzilate methobromide

[0349]

[0350] 0.96 g (0.002 mol) of 4.30 are reacted analogously to Example 1.The product is recrystallized from acetonitrile. Yield: 0.61 g of whitecrystals (59% of theory); melting point: 268° C.-269° C.; C₂₃H₂₂F₄NO₃xBr(516.33). Elemental analysis: calculated: C (53.50) H (4.29) N (2.71)found: C (53.56) H (4.38) N (2.75).

EXAMPLE 33 Scopine 4,4′-difluorobenzilate ethyl bromide

[0351]

[0352] 1.2 g (0.003 mol) of 4.8 are reacted analogously to Example 19.The product is recrystallized from ethanol. Yield: 0.93 g of whitecrystals (61% of theory); melting point: 162° C.-163° C.; C₂₄H₂₆F₂NO₄xBr(510.38). Elemental analysis: calculated: C (56.48) H (5.13) N (2.74)found: C (55.96) H (5.30) N (2.75).

EXAMPLE 34 Tropenol 3,3′-difluorobenzilate methobromide

[0353]

[0354] 1.61 g (0.004 mol) of 4.31 are reacted analogously to Example 1.The product is recrystallized from ethanol/diethylether. Yield: 1.93 gof white crystals (96% of theory); melting point: 227° C.-228° C.;C₂₃H₂₄F₂NO₃xBr (480.35). Elemental analysis: calculated: C (57.51) H(5.04) N (2.92) found: C (57.38) H (5.14) N (2.95).

EXAMPLE 35 Scopine 3,3′-difluorobenzilate methobromide

[0355]

[0356] 1.61 g (0.004 mol) of 4.32 are reacted analogously to Example 1.The product is recrystallized from ethanol. Yield: 1.83 g of whitecrystals (92% of theory); melting point: 221° C.-222° C.; C₂₃H₂₄F₂NO₄xBr(496.35). Elemental analysis: calculated: C (55.66) H (4.87) N (2.82)found: C (55.49) H (4.78) N (2.73).

EXAMPLE 36 Scopine 3,3′-dichloro-4,4′-difluorobenzilate methobromide

[0357]

[0358] 0.78 g (0.002 mol) of 4.33 are reacted analogously to Example 1.The product is recrystallized from acetonitrile. Yield: 0.67 g of whitecrystals (59% of theory); C₂₃H₂₂Cl₂F₂NO₄xBr (565.24). Elementalanalysis: calculated: C (48.87) H (3.92) N (2.48) found: C (48.87) H(3.81) N (2.46).

EXAMPLE 37 Scopine 4,4′-dichloro-3,3′-difluorobenzilate methobromide

[0359]

[0360] 2.4 g (0.0051 mol) of 4.35 are reacted analogously to Example I.The product is recrystallized from acetonitrile. Yield: 2.45 g of whitecrystals (85% of theory); melting point: 211° C.-212° C.;C₂₃H₂₂Cl₂F₂NO₄xBr (565.24).

EXAMPLE 38 Tropenol 3,3′,4,4′-tetrachlorobenzilate methobromide

[0361]

[0362] 1.8 g (0.00369 mol) of 4.36 are reacted analogously to Example 1.The product is recrystallized from methanol/diethylether. Yield: 2.01 gof white crystals (93% of theory); melting point: 245° C.-246° C.;C₂₃H₂₂Cl₄NO₃xBr (582.15). Elemental analysis: calculated: C (47.45) H(3.81) N (2.41) found: C (47.27) H (3.82) N (2.36).

EXAMPLE 39 Tropenol 4,4′-dichloro-3,3′-difluorobenzilate methobromide

[0363]

[0364] 2.5 g (0.0055 mol) of 4.34 are reacted analogously to Example 1.The product is recrystallized from acetonitrile. Yield: 1.53 g of whitecrystals (51% of theory); melting point: 229° C.-231° C.;C₂₃H₂₂Cl₂F₂NO₃xBr (549.24).

EXAMPLE 40 Tropenol 3,3′,4,4′,5,5′-tetrafluorobenzilate methobromide

[0365]

[0366] 1.7 g (0.0037 mol) of 4.37 are reacted analogously to Example 1.The product is extracted from acetone. Yield: 1.9 g of white crystals(92% of theory); melting point: 241° C.-242° C.; C₂₃H₂₀F₆NO₃xBr(552.32). Elemental analysis: calculated: C (50.02) H (3.65) N (2.54)found: C (50.09) H (3.61) N (2.49).

[0367] As has been found, the compounds of general formula 1 arecharacterized by their versatility in therapeutic use. Particularmention should be made of those applications for which the compounds offormula 1 according to the invention are preferably used on the basis oftheir pharmaceutical activity as anticholinergic agents.

[0368] These include, for example, the treatment of asthma or COPD(chronic obstructive pulmonary disease). The compounds of generalformula 1 may also be used to treat vagally induced sinus bradycardiaand to treat heart rhythm disorders. In general, the compounds accordingto the invention may also be used to treat spasms, e.g., in thegastrointestinal tract, with therapeutic benefit. They may also be usedin the treatment of spasms in the urinary tract and in menstrualdisorders, for example.

[0369] Of the ranges of indications mentioned above, the treatment ofasthma and COPD using the compounds of formula 1 according to theinvention is of particular importance.

[0370] The compounds of general formula 1 may be used on their own orcombined with other active substances of formula 1 according to theinvention.

[0371] The compounds of general formula 1 may optionally also becombined with other pharmacologically active substances. These include,in particular, betamimetics, antiallergic agents, PAF-antagonists,leukotriene-antagonists, and corticosteroids, and combinations of theseactive substances.

[0372] Examples of betamimetics which may be used in conjunction withthe compounds of formula 1 according to the invention include compoundsselected from among bambuterol, bitolterol, carbuterol, clenbuterol,fenoterol, formoterol, hexoprenaline, ibuterol, pirbuterol, procaterol,reproterol, salmeterol, sulfonterol, terbutaline, tulobuterol,4-hydroxy-7-[2-{[2-{[3-(2-phenylethoxy)propyl]sulfonyl}ethyl]-amino}ethyl]-2(3H)-benzothiazolone,1-(2-fluoro-4-hydroxyphenyl)-2-[4-(1-benzimidazolyl)-2-methyl-2-butylamino]ethanol,1-[3-(4-methoxybenzyl-amino)-4-hydroxyphenyl]-2-[4-(1-benzimidazolyl)-2-methyl-2-butylamino]ethanol,1-[2H-5-hydroxy-3-oxo-4H-1,4-benzoxazin-8-yl]-2-[3-(4-N,N-dimethylaminophenyl)-2-methyl-2-propylamino]ethanol,1-[2H-5-hydroxy-3-oxo-4H-1,4-benzoxazin-8-yl]-2-[3-(4-methoxyphenyl)-2-methyl-2-propylamino]ethanol,1-[2H-5-hydroxy-3-oxo-4H-1,4-benzoxazin-8-yl]-2-[3-(4-n-butyloxyphenyl)-2-methyl-2-propylamino]ethanol,1-[2H-5-hydroxy-3-oxo-4H-1,4-benzoxazin-8-yl]-2-{4-[3-(4-methoxyphenyl)-1,2,4-triazol-3-yl]-2-methyl-2-butylamino}ethanol,5-hydroxy-8-(1-hydroxy-2-isopropylaminobutyl)-2H-1,4-benzoxazin-3-(4H)-on,1-(4-amino-3-chloro-5-trifluoromethylphenyl)-2-tert-butylamino)ethanol,and1-(4-ethoxycarbonylamino-3-cyano-5-fluorophenyl)-2-(tert-butylamino)ethanol,optionally in the form of their racemates, their enantiomers, theirdiastereomers, as well as optionally their pharmacologically acceptableacid addition salts and hydrates. It is particularly preferable to use,as betamimetics, active substances of this kind, combined with thecompounds of formula 1 according to the invention, selected from amongfenoterol, formoterol, salmeterol,1-[3-(4-methoxybenzyl-amino)-4-hydroxyphenyl]-2-[4-(1-benzimidazolyl)-2-methyl-2-butylamino]ethanol,1-[2H-5-hydroxy-3-oxo-4H-1,4-benzoxazin-8-yl]-2-[3-(4-N,N-dimethylaminophenyl)-2-methyl-2-propylamino]ethanol,1-[2H-5-hydroxy-3-oxo-4H-1,4-benzoxazin-8-yl]-2-[3-(4-methoxyphenyl)-2-methyl-2-propylamino]ethanol,1-[2H-5-hydroxy-3-oxo-4H-1,4-benzoxazin-8-yl]-2-[3-(4-n-butyloxyphenyl)-2-methyl-2-propylamino]ethanol,1-[2H-5-hydroxy-3-oxo-4H-1,4-benzoxazin-8-yl]-2-{4-[3-(4-methoxyphenyl)-1,2,4-triazol-3-yl]-2-methyl-2-butylamino}ethanol,optionally in the form of their racemates, their enantiomers, theirdiastereomers, as well as optionally their pharmacologically acceptableacid addition salts and hydrates. Of the betamimetics mentioned above,the compounds formoterol and salmeterol, optionally in the form of theirracemates, their enantiomers, their diastereomers, as well as optionallytheir pharmacologically acceptable acid addition salts and hydrates, areparticularly important.

[0373] The acid addition salts of the betamimetics selected from amongthe hydrochloride, hydrobromide, sulfate, phosphate, fumarate,methanesulfonate, and xinafoate are preferred according to theinvention. In the case of salmeterol, the salts selected from among thehydrochloride, sulfate, and xinafoate are particularly preferred,especially the sulfates and xinafoates. Of outstanding importanceaccording to the invention are salmeterol x ½H₂SO₄ and salmeterolxinafoate. In the case of formoterol, the salts selected from among thehydrochloride, sulfate, and fumarate are particularly preferred,especially the hydrochloride and fumarate. Of outstanding importanceaccording to the invention is formoterol fumarate.

[0374] Within the scope of the present invention, the termcorticosteroids, which is optionally used in conjunction with thecompounds of formula 1, denotes compounds selected from amongflunisolide, beclomethasone, triamcinolone, budesonide, fluticasone,mometasone, ciclesonide, rofleponide, GW 215864, KSR 592, ST-126 anddexamethasone. The preferred corticosteroids within the scope of thepresent invention are those selected from among flunisolide,beclomethasone, triamcinolone, budesonide, fluticasone, mometasone,ciclesonide, and dexamethasone, while budesonide, fluticasone,mometasone, and ciclesonide, especially budesonide and fluticasone, areof particular importance. The term steroids may be used on its own,within the scope of the present patent application, instead of the termcorticosteroids. Any reference to steroids within the scope of thepresent invention also includes a reference to salts or derivativeswhich may be formed from the steroids. Examples of possible salts orderivatives include: sodium salts, sulfobenzoates, phosphates,isonicotinates, acetates, propionates, dihydrogen phosphates,palmitates, pivalates, or furoates. The corticosteroids may optionallyalso be in the form of their hydrates.

[0375] Within the scope of the present invention, the term dopamineagonists, which is optionally used in conjunction with the compounds offormula 1, denotes compounds selected from among bromocriptine,cabergoline, α-dihydroergocryptine, lisuride, pergolide, pramipexole,roxindole, ropinirole, talipexole, terguride, and viozan. It ispreferable within the scope of the present invention to use, ascombination partners with the compounds of formula 1, dopamine agonistsselected from among pramipexole, talipexole, and viozan, pramipexolebeing of particular importance. Any reference to the abovementioneddopamine agonists also includes, within the scope of the presentinvention, a reference to any pharmacologically acceptable acid additionsalts and hydrates thereof which may exist. By the physiologicallyacceptable acid addition salts thereof which may be formed by theabovementioned dopamine agonists are meant, for example,pharmaceutically acceptable salts selected from among the salts ofhydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid,methanesulfonic acid, acetic acid, fumaric acid, succinic acid, lacticacid, citric acid, tartaric acid, and maleic acid.

[0376] Examples of antiallergic agents which may be used according tothe invention as a combination with the compounds of formula 1 includeepinastine, cetirizine, azelastine, fexofenadine, levocabastine,loratadine, mizolastine, ketotifen, emedastine, dimethindene,clemastine, bamipine, dexchlorpheniramine, pheniramine, doxylamine,chlorphenoxamine, dimenhydrinate, diphenhydramine, promethazine,ebastine, desloratidine, and meclizine. Preferred antiallergic agentswhich may be used within the scope of the present invention incombination with the compounds of formula 1 according to the inventionare selected from among epinastine, cetirizine, azelastine,fexofenadine, levocabastine, loratadine, ebastine, desloratidine, andmizolastine, epinastine and desloratidine being particularly preferred.Any reference to the abovementioned antiallergic agents also includes,within the scope of the present invention, a reference to anypharmacologically acceptable acid addition salts thereof which mayexist.

[0377] The following are examples of PAF antagonists which may be usedin conjunction with the compounds of formula 1 according to theinvention:

[0378] (a)4-(2-chlorophenyl)-9-methyl-2-[3(4-morpholinyl)-3-propanon-1-yl]-6H-thieno-[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine,and

[0379] (b)6-(2-chlorophenyl)-8,9-dihydro-1-methyl-8-[(4-morpholinyl)carbonyl]-4H,7H-cyclopenta-[4,5]thieno-[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine.

[0380] Suitable preparations for administering the compounds of formula1 include tablets, capsules, suppositories, solutions, etc.

[0381] Of particular importance according to the invention (particularlywhen treating asthma or COPD) is the administration of the compoundsaccording to the invention by inhalation. The proportion ofpharmaceutically active compound or compounds should be in the rangefrom 0.05 to 90% by weight, preferably 0.1 to 50% by weight of the totalcomposition. Suitable tablets may be obtained, for example, by mixingthe active substance(s) with known excipients, for example inertdiluents such as calcium carbonate, calcium phosphate, or lactose,disintegrants such as corn starch or alginic acid, binders such asstarch or gelatine, lubricants such as magnesium stearate or talc and/oragents for delaying release, such as carboxymethyl cellulose, celluloseacetate phthalate, or polyvinyl acetate. The tablets may also compriseseveral layers.

[0382] Coated tablets may be prepared accordingly by coating coresproduced analogously to the tablets with substances normally used fortablet coatings, for example, collidone or shellac, gum arabic, talc,titanium dioxide, or sugar. To achieve delayed release or preventincompatibilities the core may also consist of a number of layers.Similarly the tablet coating may consist of a number or layers toachieve delayed release, possibly using the excipients mentioned abovefor the tablets.

[0383] Syrups or elixirs containing the active substances orcombinations thereof according to the invention may additionally containa sweetener such as saccharine, cyclamate, glycerol, or sugar and aflavor enhancer, e.g., a flavoring such as vanillin or orange extract.They may also contain suspension adjuvants or thickeners such as sodiumcarboxymethyl cellulose, wetting agents such as, for example,condensation products of fatty alcohols with ethylene oxide, orpreservatives such as p-hydroxybenzoates.

[0384] Solutions are prepared in the usual way, e.g., with the additionof isotonic agents, preservatives such as p-hydroxybenzoates, orstabilizers such as alkali metal salts of ethylenediamine tetraaceticacid, optionally using emulsifiers and/or dispersants, whilst if wateris used as the diluent, for example, optionally organic solvents isoptionally used as solvating agents or dissolving aids, and transferredinto injection vials or ampoules or infusion bottles.

[0385] Capsules containing one or more active substances or combinationsof active substances may for example be prepared by mixing the activesubstances with inert carriers such as lactose or sorbitol and packingthem into gelatine capsules.

[0386] Suitable suppositories may be made for example by mixing withcarriers provided for this purpose, such as neutral fats orpolyethyleneglycol or the derivatives thereof.

[0387] Excipients which may be used include, for example, water,pharmaceutically acceptable organic solvents such as paraffins (e.g.,petroleum fractions), vegetable oils (e.g., groundnut or sesame oil),mono- or polyfunctional alcohols (e.g., ethanol or glycerol), carrierssuch as e.g., natural mineral powders (e.g., kaolins, clays, talc,chalk), synthetic mineral powders (e.g., highly dispersed silicic acidand silicates), sugars (e.g., cane sugar, lactose, and glucose),emulsifiers (e.g., lignin, spent sulfite liquors, methylcellulose,starch, and polyvinylpyrrolidone) and lubricants (e.g., magnesiumstearate, talc, stearic acid, and sodium lauryl sulfate).

[0388] The preparations are administered by the usual methods,preferably by inhalation in the treatment of asthma or COPD. For oraladministration the tablets may, of course, contain, apart from theabovementioned carriers, additives such as sodium citrate, calciumcarbonate, and dicalcium phosphate together with various additives suchas starch, preferably potato starch, gelatine, and the like. Moreover,lubricants such as magnesium stearate, sodium lauryl sulfate, and talcmay be used at the same time for the tabletting process. In the case ofaqueous suspensions the active substances may be combined with variousflavor enhancers or colorings in addition to the excipients mentionedabove.

[0389] The dosage of the compounds according to the invention isnaturally greatly dependent on the route of administration and thecomplaint to be treated. When administered by inhalation the compoundsof formula 1 are characterized by high efficacy even at doses in the μgrange. The compounds of formula 1 can also be used effectively above theμg range. The dosage may then be in the gram range, for example.Particularly when administered by a method other than inhalation, thecompounds according to the invention may be given in higher doses (inthe range from 1 mg to 1000 mg, for example, although this does notimply any limitation).

[0390] The examples of formulations which follow illustrate the presentinvention without restricting its scope:

EXAMPLES OF PHARMACEUTICAL FORMULATIONS

[0391] A. Tablets Containing 100 mg of Active Substance Component Amountper tablet (mg) active substance 100 lactose 140 corn starch 240polyvinylpyrrolidone  15 magnesium stearate  5 TOTAL 500

[0392] The finely ground active substance, lactose, and some of the cornstarch are mixed together. The mixture is screened, then moistened witha solution of polyvinylpyrrolidone in water, kneaded, wet-granulated,and dried. The granules, the remaining corn starch and the magnesiumstearate are screened and mixed together. The mixture is compressed toproduce tablets of suitable shape and size. B. Tablets Containing 80 mgof Active Substance Component Amount per tablet (mg) active substance 80 lactose  55 corn starch 190 microcrystalline cellulose  35polyvinylpyrrolidone  15 sodium-carboxymethyl starch  23 magnesiumstearate  2 TOTAL 400

[0393] The finely ground active substance, some of the corn starch,lactose, microcrystalline cellulose, and polyvinylpyrrolidone are mixedtogether, the mixture is screened and worked with the remaining cornstarch and water to form a granulate which is dried and screened. Thesodium carboxymethyl starch and the magnesium stearate are added andmixed in and the mixture is compressed to form tablets of a suitablesize. C. Ampoules Containing 50 mg of Active Substance Component Amountactive substance 50.0 mg sodium chloride 50 mg water for inj. 5 ml

[0394] The active substance is dissolved in water at its own pH oroptionally at pH 5.5 to 6.5 and sodium chloride is added to make itisotonic. The solution obtained is filtered free from pyrogens and thefiltrate is transferred under aseptic conditions into ampoules which arethen sterilized and sealed by fusion. The ampoules contain 5 mg, 25 mg,and 50 mg of active substance. D. Metering Aerosol Component Amountactive substance 0.005 sorbitan trioleate 0.1 monofluorotrichloromethaneand ad 100 difluorodichloromethane (2:3)

[0395] The suspension is transferred into a conventional aerosolcontainer with a metering valve. Preferably, 50 μl of suspension aredelivered per spray. The active substance may also be metered in higherdoses if desired (e.g., 0.02% by weight). E. Solution Component Amount(per 100 ml solution) active substance 333.3 mg formoterol fumarate333.3 mg benzalkonium chloride  10.0 mg EDTA  50.0 mg HCl (1 N) ad pH3.4

[0396] This solution may be prepared in the usual manner. F. Powder forInhalation Component Amount active substance 6 μg formoterol fumarate 6μg lactose monohydrate ad 25 mg

[0397] The powder for inhalation is produced in the usual way by mixingthe individual ingredients together. G. Powder for Inhalation ComponentAmount active substance 10 μg lactose monohydrate ad 5 mg

[0398] The powder for inhalation is produced in the usual way by mixingthe individual ingredients together.

We claim:
 1. A compound of formula 1

wherein: A is a group selected from

X⁻ is an anion with a single negative charge; R¹ and R² are eachindependently a C₁-C₄-alkyl optionally substituted with hydroxy orhalogen; and R³, R⁴, R⁵, R⁶, R⁷, and R⁸ are each independently hydrogen,C₁-C₄-alkyl, C₁-C₄-alkyloxy, hydroxy, CF₃, CN, NO₂, or halogen, with theproviso that at least one of the groups R³, R⁴, R⁵, R⁶, R⁷, and R⁸ isnot hydrogen.
 2. The compounds of formula 1 according to claim 1,wherein: X⁻ is an anion selected from the group consisting of chloride,bromide, methylsulfate, 4-toluenesulfonate, and methanesulfonate; R¹ andR² are each independently a group selected from the group consisting ofmethyl, ethyl, n-propyl, and isopropyl, each optionally substituted byhydroxy or fluorine; and R³, R⁴, R⁵, R⁶, R⁷, and R⁸ are eachindependently hydrogen, methyl, ethyl, methyloxy, ethyloxy, hydroxy,fluorine, chlorine, bromine, CN, CF₃, or NO₂.
 3. The compound of formula1 according to claim 1, wherein: X⁻ is bromide; R¹ and R² are eachindependently methyl or ethyl; and R³, R⁴, R⁵, R⁶, R⁷, and R⁸ are eachindependently hydrogen, methyl, methyloxy, fluorine, chlorine, orbromine.
 4. The compound of formula 1 according to claim 3, wherein: R³,R⁴, R⁵, R⁶, R⁷, and R⁸ are each independently hydrogen, fluorine,chlorine, or bromine.
 5. The compound of formula 1 according to claim 4,wherein: A is a group selected from


6. The compound of formula 1 according to claim 5, wherein: R¹ and R²are each methyl; and R³, R⁴, R⁵, R⁶, R⁷, and R⁸ are each independentlyhydrogen or fluorine.
 7. A pharmaceutical composition comprising acompound of formula 1 according to claim 1 and a pharmaceuticallyacceptable excipient and/or carrier.
 8. A pharmaceutical compositioncomprising a compound of formula 1 according to claim 2 and apharmaceutically acceptable excipient and/or carrier.
 9. Apharmaceutical composition comprising a compound of formula 1 accordingto claim 3 and a pharmaceutically acceptable excipient and/or carrier.10. A pharmaceutical composition comprising a compound of formula 1according to claim 4 and a pharmaceutically acceptable excipient and/orcarrier.
 11. A pharmaceutical composition comprising a compound offormula 1 according to claim 5 and a pharmaceutically acceptableexcipient and/or carrier.
 12. A pharmaceutical composition comprising acompound of formula 1 according to claim 6 and a pharmaceuticallyacceptable excipient and/or carrier.
 13. The pharmaceutical compositionaccording to claim 7, further comprising an additional active substanceselected from the group consisting of betamimetics, antiallergic agents,PAF-antagonists, leukotriene-antagonists, and steroids.
 14. Thepharmaceutical composition according to claim 8, further comprising anadditional active substance selected from the group consisting ofbetamimetics, antiallergic agents, PAF-antagonists,leukotriene-antagonists, and steroids.
 15. The pharmaceuticalcomposition according to claim 9, further comprising an additionalactive substance selected from the group consisting of betamimetics,antiallergic agents, PAF-antagonists, leukotriene-antagonists, andsteroids.
 16. The pharmaceutical composition according to claim 10,further comprising an additional active substance selected from thegroup consisting of betamimetics, antiallergic agents, PAF-antagonists,leukotriene-antagonists, and steroids.
 17. The pharmaceuticalcomposition according to claim 11, further comprising an additionalactive substance selected from the group consisting of betamimetics,antiallergic agents, PAF-antagonists, leukotriene-antagonists, andsteroids.
 18. The pharmaceutical composition according to claim 12,further comprising an additional active substance selected from thegroup consisting of betamimetics, antiallergic agents, PAF-antagonists,leukotriene-antagonists, and steroids.
 19. A method of treating diseasesin which anticholinergics may provide a therapeutic benefit, comprisingadministering to a host in need of such treatment a compound of formula1 according to claim
 1. 20. A method of treating diseases in whichanticholinergics may provide a therapeutic benefit, comprisingadministering to a host in need of such treatment a compound of formula1 according to claim
 2. 21. A method of treating diseases in whichanticholinergics may provide a therapeutic benefit, comprisingadministering to a host in need of such treatment a compound of formula1 according to claim
 3. 22. A method of treating diseases in whichanticholinergics may provide a therapeutic benefit, comprisingadministering to a host in need of such treatment a compound of formula1 according to claim
 4. 23. A method of treating diseases in whichanticholinergics may provide a therapeutic benefit, comprisingadministering to a host in need of such treatment a compound of formula1 according to claim
 5. 24. A method of treating diseases in whichanticholinergics may provide a therapeutic benefit, comprisingadministering to a host in need of such treatment a compound of formula1 according to claim
 6. 25. A method of treating asthma, COPD, vagallyinduced sinus bradycardia, heart rhythm disorders, spasms in thegastrointestinal tract, spasms in the urinary tract, or menstrualdisorders, comprising administering to a host in need of such treatmenta compound of formula 1 according to claim
 1. 26. A method of treatingasthma, COPD, vagally induced sinus bradycardia, heart rhythm disorders,spasms in the gastrointestinal tract, spasms in the urinary tract, ormenstrual disorders, comprising administering to a host in need of suchtreatment a compound of formula 1 according to claim
 2. 27. A method oftreating asthma, COPD, vagally induced sinus bradycardia, heart rhythmdisorders, spasms in the gastrointestinal tract, spasms in the urinarytract, or menstrual disorders, comprising administering to a host inneed of such treatment a compound of formula 1 according to claim
 3. 28.A method of treating asthma, COPD, vagally induced sinus bradycardia,heart rhythm disorders, spasms in the gastrointestinal tract, spasms inthe urinary tract, or menstrual disorders, comprising administering to ahost in need of such treatment a compound of formula 1 according toclaim
 4. 29. A method of treating asthma, COPD, vagally induced sinusbradycardia, heart rhythm disorders, spasms in the gastrointestinaltract, spasms in the urinary tract, or menstrual disorders, comprisingadministering to a host in need of such treatment a compound of formula1 according to claim
 5. 30. A method of treating asthma, COPD, vagallyinduced sinus bradycardia, heart rhythm disorders, spasms in thegastrointestinal tract, spasms in the urinary tract, or menstrualdisorders, comprising administering to a host in need of such treatmenta compound of formula 1 according to claim
 6. 31. A compound of formula4

wherein: A is a group selected from

R¹ is a C₁-C₄-alkyl optionally substituted with hydroxy or halogen; andR³, R⁴, R⁵, R⁶, R⁷, and R⁸ are each independently hydrogen, C₁-C₄-alkyl,C₁-C₄-alkyloxy, hydroxy, CF₃, CN, NO₂, or halogen, with the proviso thatat least one of the groups R³, R⁴, R⁵, R⁶, R⁷, and R⁸ is not hydrogen.32. The compound of formula 4 according to claim 31, wherein: R¹ is agroup selected from the group consisting of methyl, ethyl, n-propyl, andisopropyl, each optionally substituted by hydroxy or fluorine; R³, R⁴,R⁵, R⁶, R⁷, and R⁸ are each independently hydrogen, methyl, ethyl,methyloxy, ethyloxy, hydroxy, fluorine, chlorine, bromine, CN, CF₃, orNO₂.
 33. The compound of formula 4 according to claim 31, wherein: R¹ ismethyl or ethyl; and R³, R⁴, R⁵, R⁶, R⁷, and R⁸ are each independentlyhydrogen, methyl, methyloxy, fluorine, chlorine, or bromine.
 34. Thecompound of formula 4 according to claim 33, wherein: R³, R⁴, R⁵, R⁶,R⁷, and R⁸ are each independently hydrogen, fluorine, chlorine, orbromine.
 35. The compound of formula 4 according to claim 31, wherein:R³, R⁴, R⁵, R⁶, R⁷, and R⁸ are each independently hydrogen or fluorine.36. A compound of formula 3

wherein: R is C₁-C₄-alkyl; and R³, R⁴, R⁵, R⁶, R⁷, and R⁸ are eachindependently hydrogen, C₁-C₄-alkyl, C₁-C₄-alkyloxy, hydroxy, CF₃, CN,NO₂, or halogen, with the proviso that at least one of the groups R³,R⁴, R⁵, R⁶, R⁷, and R⁸ is not hydrogen.
 37. The compound of formula 3according to claim 36, wherein: R³, R⁴, R⁵, R⁶, R⁷, and R⁸ are eachindependently hydrogen, methyl, ethyl, methyloxy, ethyloxy, hydroxy,fluorine, chlorine, bromine, CN, CF₃, or NO₂.
 38. The compound offormula 3 according to claim 36, wherein: R³, R⁴, R⁵, R⁶, R⁷, and R⁸ areeach independently hydrogen, methyl, methyloxy, fluorine, chlorine, orbromine.
 39. The compound of formula 3 according to claim 36, wherein:R³, R⁴, R⁵, R⁶, R⁷, and R⁸ are each independently hydrogen, fluorine,chlorine, or bromine.
 40. The compound of formula 3 according to claim36, wherein: R³, R⁴, R⁵, R⁶, R⁷, and R⁸ are each independently hydrogenor fluorine.